Background: Lung tumors are prevalent malignancies associated with a high mortality rate, imposing significant medical and societal burdens. Although immunotherapy shows promise in improving survival, response rates are relatively modest. Thermal ablation can not only eliminate tumor cells directly but also enhance antitumor immunity response, thus manifesting a remarkable propensity to synergize with immunotherapy. Summary: In this review, we provided a brief overview of the application of thermal ablation in peripheral lung tumors. We summarized the patient selection of thermal ablation. We highlighted the potential of thermal ablation to augment the antitumor immune response, offering a promising avenue for combined therapies. We summarized studies assessing the synergistic effects of thermal ablation and immunotherapy in preclinical and clinical settings. Lastly, we underscored the urgent issues that warrant in-depth exploration when applying thermal ablation and immunotherapy to lung tumor patients. Key Messages: This review emphasized the prospects of using thermal ablation combined with immunotherapy in patients with peripheral lung tumors. However, further research is needed to enhance and optimize this treatment strategy.

Lung cancer is a highly invasive and common disease that has become a worldwide public health challenge [1, 2]. Among lung cancer cases, non-small cell lung cancer (NSCLC) accounts for approximately 87% of diagnoses. Nowadays, surgical intervention stands as the gold standard treatment strategy for patients suffering from early-stage NSCLC, with a 5-year overall survival (OS) of 78.9–82% [3, 4]. For medically inoperable early-stage patients, local therapies including stereotactic ablative radiotherapy (SABR) and thermal ablation may be a feasible option [5]. For advanced NSCLC, immunotherapies have emerged as promising options [6, 7]. PD-1/PD-L1 antibodies combined or not combined with chemotherapy have been recommended as the first-line standard treatment option for patients suffering from stage IV NSCLC lacking specific gene mutations, which has significantly prolonged the life span of patients compared with chemotherapy, with a 5-year OS rate ranging from 16.6% to 31.9% [8‒12]. However, the response rate (RR) of PD-1/PD-L1 antibodies was relatively low. Additionally, patients may develop primary or secondary resistance. As a result, the progression-free survival (PFS) of patients remains relatively low, ranging from 8.1 months to 10.3 months, and the underlying mechanism remains largely unknown [7, 13‒16]. Considering that immune response is crucial in immunotherapies, local therapies that boost antitumor immunity may potentially exert synergistic effects with immunotherapies, warranting further investigation.

Research has demonstrated that SABR could synergize with immunotherapy and improve the prognosis of patients with early-stage or isolated parenchymal recurrent node-negative NSCLC compared with SABR alone [17]. In a pooled analysis, prolonged median PFS and OS have been observed in patients with metastatic NSCLC who received combined therapy of immunotherapy and radiotherapy compared with those who received immunotherapy alone [18]. Additionally, subgroup analyses of the PEMBR-RT trial demonstrated that in patients with PD-L1-negative tumors who received combined therapy of SABR and immunotherapy, a longer PFS and OS were observed compared with those who received immunotherapy alone [19]. These trials inspire us to consider that the combination of local therapy and systemic immunotherapy may offer greater benefits to patients with early-stage or advanced NSCLC. Meanwhile, local therapy may act as a tumor vaccine to make a “cold tumor” become a “hot tumor,” which may better respond to the immune response. However, the application of SABR has been limited in some situations, including previous radiotherapy, difficult anatomy, poor pulmonary function, and interstitial lung disease [20, 21]. Meanwhile, SABR is relatively expensive, requires multiple sessions, and may induce complications like radiation pneumonitis, resulting in some patients being hesitant to choose this treatment [20, 21]. In these situations, thermal ablation may be a preferable alternative to local therapy.

Thermal ablation refers to local therapy that involves the application of extremely high or low temperatures to induce apoptosis and coagulative necrosis of tumor cells, including radiofrequency ablation (RFA), microwave ablation (MWA), and cryoablation [22]. Thermal ablation has been used as a treatment option for selected patients with inoperable early-stage lung cancer, advanced lung cancer, or pulmonary metastases [23]. Thermal ablation can not only induce cell death of tumor cells directly but also evoke local and systemic antitumor immunity through the release of tumor antigens, generation of damage-associated molecular patterns, and secretion of cytokines [24]. Considering the immunomodulatory effects of thermal ablation, the combination of immunotherapy and thermal ablation may be an intriguing option to improve the prognosis of patients with lung tumors.

Here, we explored the role of percutaneous thermal ablation in patients with peripheral lung tumors, the patient selection of thermal ablation, the immunomodulatory effect of thermal ablation, and the existing body of evidence supporting the combined therapies with thermal ablation and immunotherapy. Additionally, we summarized the obstacles of combined therapy using thermal ablation and immunotherapy. Moreover, we pinpointed the urgent issues that deserve exploration in this area. In terms of methodology, we have thoroughly reviewed relevant literature and clinical trials with the keywords related to thermal ablation, lung tumors, and immunotherapy on PubMed, https://clinicaltrials.gov, and https://www.chictr.org.cn. Additional literature is included according to the reference lists of relevant articles.

Early-Stage Lung Tumors

Thermal ablation has become a valuable treatment option for individuals diagnosed with early-stage lung cancer who are unable to receive surgery due to poor cardiopulmonary function or advanced age [25]. For patients with early-stage lung cancer who are unwilling to undergo surgery or SBRT, thermal ablation can also be an excellent alternative [26]. Additionally, thermal ablation may be an option for patients with multiple primary lung tumors if there is no indication of distant or nodal metastases, the maximal tumor diameter is less than 3 cm, and the number of lung tumors is less than three [26].

Computed tomography (CT)-guided percutaneous RFA has yielded promising results in inoperable stage I NSCLC, including a 1-year OS rate of 90.5–91.67%, a 3-year OS rate of 58.33–65.5%, and an OS of 33.4–57 months [27‒29]. Additionally, for patients diagnosed with inoperable early-stage NSCLC including elderly individuals and cases involving ground-glass opacity, percutaneous CT-guided MWA seems to be a treatment alternative, offering a 1-year OS rate ranging from 89% to 97.1%, a 3-year OS rate ranging from 43% to 96% [30‒34]. Meanwhile, CT-guided cryoablation has been identified as a potentially curative and feasible therapeutic strategy for patients with early-stage lung cancer who are nonsurgical candidates, demonstrating a 2-year OS rate of 88–100%, a 5-year OS rate of 67.8% ± 15.3 [35‒37].

Advanced and Metastatic Lung Tumors

In cases of pulmonary oligometastatic tumors, if the primary tumor can be effectively controlled, thermal ablation can be applied to the pulmonary metastases [26]. Meanwhile, thermal ablation may be a feasible choice for patients with small-size lung metastases [38]. Additionally, for patients with oligoprogressive disease, thermal ablation may serve as an option for treatment-resistant tumors [39]. Moreover, palliative thermal ablation may be significant in comprehensive treatment strategies to alleviate tumor-induced symptoms, enhance patient’s quality of life, and fully extend life expectancy [40].

For patients with pulmonary metastases, CT-guided percutaneous RFA has displayed acceptable efficacy in diverse studies. A median OS ranging from 46 months to 77.1 months [41‒43] and a 3-year OS rate ranging from 50% to 60% [41, 42] have been observed with no procedure-related death. Additionally, Li et al. [44] discovered that, with a median follow-up period of 19 months, 63.3% of patients suffering from advanced NSCLC gained complete response after receiving RFA as a supplemental therapy for systemic therapy.

CT-guided MWA has exhibited great local control for patients suffering from lung metastases [45, 46]. In 44 patients with 87 pulmonary metastases, with a median follow-up of 15 months, local tumor progression was only observed in 2 of 87 tumors [46].

Cryoablation has also been applied to patients with lung metastases, demonstrating favorable results in various studies with a 1-year OS rate ranging from 97.5% to 97.6% and a 1-year local tumor control rate ranging from 85.1% to 96.6% [47, 48]. Importantly, sustained clinical benefits of cryoablation have also been observed in patients with lung metastases, exhibiting OS rates of 63.2% and 46.7% at 3 years and 5 years, respectively [49]. Furthermore, after the failure of chemoradiotherapy, Wei et al. [50] have conducted cryoablation on patients suffering from stage IIIB/IV advanced NSCLC with a 1-year OS rate of 81.8%.

Contraindications of Thermal Ablation

Given the excellent patient tolerance of thermal ablation, there are few absolute contraindications to thermal ablation, except for poor coagulation dysfunction [51]. The contraindications of thermal ablation include (1) patients with poorly controlled infection or inflammation around the lesions and puncture sites. (2) Patients suffering from severe pulmonary fibrosis [52]. (3) Patients with a severe tendency for hemorrhage, ongoing anticoagulation therapy, or clopidogrel intake [53]. (4) Patients with severe dysfunction of vital organs and severe disorders of nutrition metabolism, which cannot be improved in the short term. Additionally, patients experience severe systemic infection and high fever [26]. (5) Patients with poor Eastern Cooperative Oncology Group (ECOG) scores or a limited life expectancy are not recommended for ablation therapy [26, 51]. (6) Patients with uncontrolled malignant pleural effusion in the ablation zone [26]. (7) Patients with pacemakers or implanted defibrillators are not suggested to undergo RFA [26, 53].

Comparison of RFA, MWA, and Cryoablation

RFA was the initial ablation method introduced for the treatment of lung tumors with the most experienced physicians compared with MWA and cryoablation. However, the formation of potential charring tissue around the electrode during RFA may impact its electrical and heat conductivity, thus affecting its efficacy. Moreover, during RFA, the heat sink phenomenon can occur when the ablation zone is adjacent to large blood vessels and airways, thereby reducing the temperature within the ablation zone and influencing its effectiveness [54]. Additionally, RFA may interact with cardiac pacemakers and implantable cardioverter defibrillators. Furthermore, when tumor volume is substantial, the complete ablation rate of RFA tends to be relatively low, with tumor size exceeding 3 cm serving as a crucial prognostic factor [55]. Considering these limitations, RFA may not be suitable for patients with large tumors, tumors located near major blood vessels or airways, or patients with implanted pacemakers and implantable cardioverter defibrillators.

MWA has been reported to offer a broader field of power density and a relatively larger zone of active heating compared to RFA, making it capable of eliminating tumors more uniformly and less susceptible to the heat sink effect [56, 57]. Additionally, unlike RFA, MWA does not rely on electrical conduction, and charred tissues will not influence its efficacy. However, the nonspherical shape of the MWA ablation zone makes it challenging to predict [54]. Given these characteristics, MWA is suitable for patients with larger tumors and tumors localized near airways and large blood vessels.

Cryoablation has been noted for its low sensitivity to the heat sink effect. Additionally, studies by Allaf et al. [58] have indicated that patients undergoing cryoablation required less analgesia after surgery compared to those undergoing RFA. Moreover, Thacker et al. [59] discovered that patients receiving cryoablation for NSCLC bone metastases experienced significantly reduced postoperative pain levels compared with baseline. Furthermore, due to the relatively intact tumor cell contents after cryoablation, there may be enhanced antigen presentation to antigen-presenting cells (APCs), potentially triggering a stronger antitumor immune response compared with RFA and MWA [54]. Another advantage of cryoablation is its ability to use multiple probes for targeted tumors [54]. However, cryoablation may lead to platelet depletion and increase bleeding risk [54]. Considering these features, cryoablation may be a suitable option for patients requiring combination therapy with immunotherapy. It may also be beneficial for patients suffering from large tumors or lesions localized near airways or large vessels. For lesions within 1 cm of the pleura or exhibiting bone destruction due to bone metastases, cryoablation offers advantages over RFA and MWA [26]. Additionally, the well-defined ice ball formation during cryoablation enables easy monitoring of the ablation zone, making it applicable to lung tumors near vital organs [26]. However, cryoablation is not suitable for patients with coagulation dysfunction.

Comparison of Percutaneous Thermal Ablation and Transbronchial Thermal Ablation

Percutaneous thermal ablation has been applied in the treatment of peripheral lung tumors for a long time, and the technology is relatively mature. However, clinical practice still faces some limitations regarding this treatment modality. Percutaneous thermal ablation may encounter challenges due to the obstruction posed by bony structures such as ribs and shoulder blades during the puncture approach. Additionally, percutaneous thermal ablation inevitably causes damage to the visceral pleura, leading to a high incidence of pneumothorax. It can also result in some other documented complications including bronchopleural fistula, pleural effusion, bleeding, thermal injury to nearby structures, and needle tract seeding [21]. Moreover, the location of percutaneous thermal ablation may be influenced by the respiratory cycles.

Recently, several studies have been conducted to investigate the efficacy and safety of transbronchial thermal ablation in treating lung tumors, and good local control rates and technical success rates have been observed [60‒63]. Meanwhile, given that transbronchial thermal ablation does not invade the pleural space [64], the reported complications of transbronchial thermal ablation are relatively mild, complications like pneumothorax and bleeding have been avoided, and almost no additional hospitalization is required [61, 63, 65]. However, sometimes, due to the immaturity of the technical protocol, some unexpectedly serious complications like (non-cardiogenic) pulmonary edema may arise [60]. Moreover, experiments regarding transbronchial thermal ablation are still in the early stage, with most current studies being small and short-term. The long-term safety and effectiveness of this technology remain unclear. Additionally, several technical challenges hinder the widespread adoption of transbronchial thermal ablation, including the ability to navigate to the targets, appropriate localization of the ablative probe near the targeted tumor, and accurate prediction of the ablation zone [64]. Nowadays, with the development of technology, several bronchoscopic techniques have enhanced our ability to access targeted lesions, including navigational (both electromagnetic and non-electromagnetic) bronchoscope, radial-probe endobronchial ultrasound, robotic bronchoscopy, and notably cone beam CT [63, 64]. Cone beam CT can not only assist us in navigating to targeted lesions and confirming accurate positioning but also holds the potential for evaluating ablation efficacy and identifying intraoperative complications [64, 66]. Bronchoscopic transparenchymal nodule access facilitates the reach of pulmonary lesions without utilizing the bronchial route, establishing a direct tunnel through the lung parenchyma into the lesion [67]. In the future, integrating these techniques with transbronchial thermal ablation could further benefit a larger patient population.

In conclusion, percutaneous thermal ablation appears to be an effective clinical option for patients who are not appropriate for surgery. However, large-scale, long-term clinical trials with multiple subgroups are needed for further guiding the individual selection of ablation modalities and the precise selection of populations that benefit most from ablation therapy. Meanwhile, the emergence of transbronchial thermal ablation represents an innovative approach that may potentially reduce complications, particularly pneumothorax and hemothorax in patients with lung tumors. However, additional research is essential to assess the feasibility of transbronchial thermal ablation and compare it directly with percutaneous thermal ablation in the setting of lung tumors. Additionally, accurate navigation is significant in guiding transbronchial thermal ablation, and the combination of innovative bronchoscopic techniques with transbronchial thermal ablation needs to be further investigated.

RFA

RFA can influence tissue immunogenicity in various ways. The necrotic tumor cells generated by RFA act as a source of intracellular antigens. Additionally, the surviving cells, having been exposed to heat shock during the procedure, induce an upregulation of heat shock proteins (HSPs). Moreover, the trauma induced by RFA contributes to local inflammation. All these factors collectively lead to the maturation and activation of APCs and evoke antitumor immune responses [68].

Through analysis of peripheral blood samples from patients with lung tumors undergoing RFA, Fietta et al. [69] demonstrated that 3 days after RFA increased levels of neutrophils, monocytes, and acute phase reactants were observed. Additionally, several chemokines upregulated 3 days after RFA and returned to pre-RFA levels 30 days after RFA, for example, proinflammatory chemokines (including MIP-1alpha, MIP-1beta, eotaxin, and interleukin (IL)-8) and anti-inflammatory factor IL-10. Notably, there was an augmentation of cluster of differentiation (CD) 4+ T cells and interferon-gamma (IFN-γ)-secreting cells observed 30 days after RFA. What is more, reductions in the levels of immunosuppressive CD25+ forkhead box protein P3 (Foxp3)+ cells were observed, which persisted from day 30 to day 90 after RFA [69]. Schneider T and colleagues found that NSCLC patients who experienced relapse after RFA exhibited rising serum levels of tumor necrosis factor-α (TNF-α), C-C motif chemokine 2 (CCL-2), and C-C motif chemokine 4 (CCL-4) when compared to patients without relapse. This increase was potentially related to elevated levels of nitric oxide production in myeloid-derived suppressor cells (MDSCs) [70]. Shaobin et al. [71] investigated changes in CD4 subsets after RFA and revealed that the levels of T helper (Th) 1 cells and Th1/Th2 ratios elevated, accompanied by reductions in the levels of Th2, Th17, and Treg cells 2 weeks after RFA. These changes reflected an enhancement of antitumor immunity [71]. Meanwhile, they found that these changes in CD4 subsets were more pronounced with larger RFA treatment areas. Schneider et al. [72] found that in patients with NSCLC who have undergone RFA, infiltrations of CD4+ and CD8+ lymphocytes were increased around the margin of the RFA-treated region, while the central area of the tumor remained lacking lymphocytes. In the peripheral blood, releasement of proinflammatory, immunostimulatory cytokine IFN-γ augmented, immunostimulatory blood dendritic cell antigen-3+/B7 homolog3 dendritic cells (DCs) raised, and T-cell proliferation increased significantly 3 days after RFA [72]. HSP70, a crucial alarm signal for the immune system that can induce the activation of antitumor T-cell immunity, was observed to increase in the serum of cancer patients 1 day after RFA [73]. Additionally, enhancement of HSP70 after RFA was also associated with a favorable prognosis [73].

MWA

Heat injury caused by MWA can induce direct cellular damage through altering cell membrane integrity, causing mitochondrial dysfunction, and inhibiting DNA replication, which may further lead to the release of lysosomal contents from necrotic tumor cells or infiltrating granulocytes, the secretion of cytokines, and further stimulation of an immune response [22].

Zhang et al. [74] conducted an analysis of peripheral blood samples from patients with pulmonary cancer on the day before (D0) and 1 month (M1) after MWA. Data indicated an increase in the proportion of CD 8+ T cells, rising from 22.95 ± 7.38% (D0) to 25.95 ± 9.16% (M1), and a decrease in the proportion of regulatory T (Treg) cells, dropping from 10.82 ± 4.52% (D0) to 8.77 ± 2.05% (M1), and a reduction in the IL-2 concentration, which decreased from 1.58 ± 0.46 pg/mL (D0) to 1.26 ± 0.60 pg/mL (M1). What is more, the decrease in the proportion of Treg cells was related to improved PFS independently [74]. However, an examination of plasma samples from patients with primary NSCLC demonstrated that the levels of IL-2 and IFN-γ were initially downregulated at 48 h after MWA and then upregulated at 1 month after MWA [75]. The inconsistent trend in IL-2 concentration changes at 1 month after MWA in the two studies remains largely unexplained and may be partially attributed to differences in the enrolled patients. Xu et al. [76] observed that a patient with lung metastases from endometrial carcinoma experienced shrinkage of other untreated lesions after the local MWA of one lesion, which may result from the activation of systemic immune response by MWA.

Cryoablation

Cryoablation can regulate immunity response via various mechanisms. In the central part of the cryoablation zone, cell necrosis occurs, contributing to the secretion of danger signals such as DNA, RNA, and HSP70. Danger signals can induce the initiation of immune response through maturing dendritic cells, which in turn activate T cells [77]. Conversely, in the marginal area of cryoablation, cells undergo apoptosis without secretion of danger signals. APCs recognize these cells in a major histocompatibility complex (MHC) class I molecules dependent and co-stimulatory molecules independent way which may further lead to anergy and clonal deletion of T cells [22, 77]. Additionally, studies revealed that cell death induced by cryoablation can provide relatively intact antitumor antigens. This is due to the destruction of the cell plasma membrane while maintenance of intact intracytoplasmic organelles and the cell ultrastructure [78, 79]. Moreover, with different freeze rates, cryoablation can result in the secretion of immunostimulatory and immunosuppressive cytokines [80].

In mouse models implanted with Lewis lung carcinoma cells, elevated proportions of CD4+ T cells and CD8+ T cells were observed after two cycles of cryoablation. Additionally, there was a significant upregulation of proinflammatory cytokines [81]. Yang et al. [82] also discovered that, in mice bearing tumors, the killing activity of cytotoxic T lymphocytes and nature killer cells increased after cryoablation, which further decreased the pulmonary metastasis rate. Gu et al. [83] demonstrated that cryoablation significantly upregulated circulating CD8+ T cells and proinflammatory cytokines in patients with early-stage NSCLC. Meanwhile, they revealed that in mice implanted with KrasG12D/+, Tp53−/− (KP) mutant lung cancer cells undergoing cryoablation, the intertumoral immune microenvironment of non-ablated tumors was reprogrammed. Infiltration, cytolytic activity, and effector signature of CD8+ T cell have significantly augmented after cryoablation. Mechanistically, cryoablation promoted the antitumor effect dependent on the STING-dependent type I IFN signaling pathway [83].

Summarily, thermal ablation can regulate antitumor immunity responses in individuals with lung tumors. This regulation is characterized by an augment in APCs, enhanced levels of immunostimulant Th1 cells and CD8+ T cells, as well as downregulation of immunosuppressive Th2 cells and Treg cells (shown in Table 1). These immunomodulatory effects of thermal ablation are attributed to the production of tumor antigens, the release of danger signals, and the secretion of cytokines (shown in Fig. 1). However, it is important to note that studies on immune responses after thermal ablation in lung tumors are currently limited. What is more, most studies have concentrated on the early post-ablation period, and the long-term impact of thermal ablation on the immune system remains unclear. Therefore, more extensive research is needed to directly compare the immune responses following different ablation treatments at various time points after thermal ablation and in diverse populations undergoing ablation treatment, which may broaden our horizons in the immunomodulatory effect of thermal ablation and guide us in effectively combining thermal ablation with immunotherapy. Additionally, the relationship between immune responses after thermal ablation and patient prognosis still needs to be further investigated.

Table 1.

Immunomodulatory effect of thermal ablation in patients with lung tumors

Author, yearAblation typeImmunomodulatory effectSample source
Fietta et al. [69] (2009) RFA Three days after RFA increased levels of neutrophils, monocytes, and acute phase reactants have been observed. Additionally, several proinflammatory and anti-inflammatory chemokines have upregulated 3 days after RFA and returned to pre-RFA levels 30 days after RFA. Moreover, augmentation of CD 4+ T cells and cells that secrete interferon-gamma has been observed at 30 days after RFA. What is more, the level of CD25+ Foxp3+ cells downregulated and lasted from day 30 to day 90 after RFA. Peripheral blood samples 
Shaobin et al. [71] (2016) RFA The levels of Th1 cells and Th1/Th2 elevated with a reduction in the levels of Th2, Th17, and Treg cells 2 weeks after RFA. Meanwhile, the change of the CD4 subset is more obvious with larger regions of RFA. Peripheral blood samples 
Schneider et al. [72] (2016) RFA After RFA, infiltrations of CD4+ and CD8+ lymphocytes were increased around the margin of the RFA-treated region, while the central area of the tumor remained lacking lymphocytes. In the peripheral blood, releasement of IFN-γ augmented, immunostimulatory blood dendritic cell antigen-3+/B7 homolog3 DCs raised, and T-cell proliferation increased significantly 3 days after RFA. Tumor tissue and peripheral blood samples 
Haen et al. [73] (2011) RFA HSP70 which can induce activation of antitumor T-cell immunity has been observed to increase in the serum of cancer patients 1 day after RFA. Peripheral blood samples 
Zhang et al. [74] (2022) MWA The proportion of CD8+ T cells upregulated, the proportion of Treg cells downregulated and the IL-2 concentration decreased after MWA. Peripheral blood samples 
Xu et al. [75] (2022) MWA Levels of IL-2 and IFN-γ were downregulated at 48 h after MWA and upregulated at 1 month after MWA. Peripheral blood samples 
Gu et al. [83] (2024) Cryoablation Cryoablation significantly upregulated circulating CD8+ T cells and proinflammatory cytokines in patients with early-stage NSCLC Peripheral blood samples 
Author, yearAblation typeImmunomodulatory effectSample source
Fietta et al. [69] (2009) RFA Three days after RFA increased levels of neutrophils, monocytes, and acute phase reactants have been observed. Additionally, several proinflammatory and anti-inflammatory chemokines have upregulated 3 days after RFA and returned to pre-RFA levels 30 days after RFA. Moreover, augmentation of CD 4+ T cells and cells that secrete interferon-gamma has been observed at 30 days after RFA. What is more, the level of CD25+ Foxp3+ cells downregulated and lasted from day 30 to day 90 after RFA. Peripheral blood samples 
Shaobin et al. [71] (2016) RFA The levels of Th1 cells and Th1/Th2 elevated with a reduction in the levels of Th2, Th17, and Treg cells 2 weeks after RFA. Meanwhile, the change of the CD4 subset is more obvious with larger regions of RFA. Peripheral blood samples 
Schneider et al. [72] (2016) RFA After RFA, infiltrations of CD4+ and CD8+ lymphocytes were increased around the margin of the RFA-treated region, while the central area of the tumor remained lacking lymphocytes. In the peripheral blood, releasement of IFN-γ augmented, immunostimulatory blood dendritic cell antigen-3+/B7 homolog3 DCs raised, and T-cell proliferation increased significantly 3 days after RFA. Tumor tissue and peripheral blood samples 
Haen et al. [73] (2011) RFA HSP70 which can induce activation of antitumor T-cell immunity has been observed to increase in the serum of cancer patients 1 day after RFA. Peripheral blood samples 
Zhang et al. [74] (2022) MWA The proportion of CD8+ T cells upregulated, the proportion of Treg cells downregulated and the IL-2 concentration decreased after MWA. Peripheral blood samples 
Xu et al. [75] (2022) MWA Levels of IL-2 and IFN-γ were downregulated at 48 h after MWA and upregulated at 1 month after MWA. Peripheral blood samples 
Gu et al. [83] (2024) Cryoablation Cryoablation significantly upregulated circulating CD8+ T cells and proinflammatory cytokines in patients with early-stage NSCLC Peripheral blood samples 

RFA, radiofrequency ablation; CD4+, cluster of differentiation 4+; CD25+, cluster of differentiation 25+; Foxp3+, forkhead box protein P3+; Th1, T helper 1; Th2, T helper 2; Th17, T helper 17; Treg, regulatory T cells; CD8+, cluster of differentiation 8+; IFN-γ, interferon-gamma; BDCA-3+, blood dendritic cell antigen-3+; B7-H3, B7 homolog3; HSP70, heat shock protein 70; IL-2, interleukin-2; MWA, microwave ablation.

Fig. 1.

Immunomodulatory effects of thermal ablation and potential combined strategies with immunotherapy. a Two approaches for the thermal ablation of lung tumors have been illustrated, namely, percutaneous and transbronchial thermal ablation. b Immunomodulatory effects of thermal ablation have been demonstrated. Thermal ablation can directly induce necrosis in tumor cells, which may further release DAMPs and tumor antigens. This, in turn, can boost the activation, proliferation, migration into tumor tissues, and cytokine release by effector T cells, consequently, exerting antitumor immune effects. Additionally, studies have revealed that thermal ablation may downregulate immune suppressive cells, including Treg and Th2 cells. The dotted line means that the mechanism by which thermal ablation downregulates Treg and Th2 levels is unclear. c Immunotherapies that hold promise for potential combination with thermal ablation have been exhibited. Various immunotherapy strategies are presented, such as Treg inhibitors, APCs and Teff activators, cellular immunotherapy, and immune checkpoint blockade. DAMP, damage-associated molecular pattern; Treg, regulatory T cells; Th2, T helper 2; IFN-γ, interferon-gamma; APC, antigen-presenting cell; DC, dendritic cell; CAR-T, chimeric antigen receptor-modified T; NK, nature killer (the figure was created with BioRender.com).

Fig. 1.

Immunomodulatory effects of thermal ablation and potential combined strategies with immunotherapy. a Two approaches for the thermal ablation of lung tumors have been illustrated, namely, percutaneous and transbronchial thermal ablation. b Immunomodulatory effects of thermal ablation have been demonstrated. Thermal ablation can directly induce necrosis in tumor cells, which may further release DAMPs and tumor antigens. This, in turn, can boost the activation, proliferation, migration into tumor tissues, and cytokine release by effector T cells, consequently, exerting antitumor immune effects. Additionally, studies have revealed that thermal ablation may downregulate immune suppressive cells, including Treg and Th2 cells. The dotted line means that the mechanism by which thermal ablation downregulates Treg and Th2 levels is unclear. c Immunotherapies that hold promise for potential combination with thermal ablation have been exhibited. Various immunotherapy strategies are presented, such as Treg inhibitors, APCs and Teff activators, cellular immunotherapy, and immune checkpoint blockade. DAMP, damage-associated molecular pattern; Treg, regulatory T cells; Th2, T helper 2; IFN-γ, interferon-gamma; APC, antigen-presenting cell; DC, dendritic cell; CAR-T, chimeric antigen receptor-modified T; NK, nature killer (the figure was created with BioRender.com).

Close modal

RFA

RFA Combined with Immunotherapy in Preclinical Settings

OK-423 is a lyophilized formulation of a low-virulence strain, Su Streptococcus pyogenes (group A), which has been inactivated using penicillin. OK-423, which can enhance antitumor T-cell responses, has been identified as an immunotherapeutic agent [84]. In a study by Hamamoto et al. [85], rabbits with lung and auricle tumors were randomly divided into four groups: control, RFA-only, OK-423 only, and combined therapy (RFA with local injection of OK-423). They observed that in comparison to the other three groups, the survival of rabbits in the combined therapy group was prolonged obviously. Notably, the regression of distant auricle tumors was only observed in the combined therapy group [85].

Mycobacterium bovis bacillus Calmette-Guérin (BCG), originally designed as a vaccine to suppress bovine tuberculosis in cattle, has been verified to offer immunotherapeutic benefit in the context of tumors and has been regarded as an immunostimulant [86, 87]. In another study by Hamamoto and colleagues [87], rabbits with lung and auricle tumors were randomized into three groups: no treatment, RFA-only, and RFA with local injection of BCG. The results showed that the median survival times for the control, RFA-only, and RFA with BCG groups were 23, 41.5, and 103.5 days, respectively. Importantly, the suppression of remote tumors was only observed in the group that received the combined treatment of RFA and local injection of BCG, not in the RFA-alone group [87].

Xu et al. [88] discovered that the administration of 4 cytosine-phosphorothioate-guanine (CpG), a Toll-like receptor 9 (TLR9) agonist, in combination with RFA, led to elevated levels of tumor-associated immunogenic CD11bCD11c+CD103+DC2 and CD11b+F4/80+MHCII+M1 macrophages. This combination treatment also promoted the infiltration of CD4+ and CD8+ T cells into the tumors, contributing to intense CD4+ T-cell-dependent CTL responses which may further restrict the growth of remote tumors and inhibit lung metastasis, surpassing the effects of RFA alone [88].

Furthermore, intragastrical administration of fosbretabulin disodium before RFA has been verified to upregulate RFA-induced IFN-γ+ and TNF-α+ CD8+ tumor-infiltrating lymphocytes through downregulating RFA-induced expression of PD-1 and PD-L1 [89]. Li et al. [90] discovered that melatonin can augment RFA-induced NK activity and exhibit synergistic antitumor effects with RFA which can regress tumor growth in non-ablated regions in mice bearing lung tumors.

RFA Combined with Immunotherapy in Clinical Settings

Li et al. [90] found that for patients suffering from early lung cancer with multiple pulmonary nodules, the combination of RFA and melatonin can improve their clinical outcomes. This combination therapy was associated with the suppression of non-ablated nodules and a reduction in complications compared to surgery alone [90]. Yin et al. [91] reported an intriguing case involving a patient with stage IV NSCLC. This patient exhibited an obvious response to atezolizumab, a PD-L1 antibody, in the region of the lung that had previously undergone RFA. In contrast, there was little response to atezolizumab in lung lesions that had not received RFA, indicating a substantial synergistic effect of RFA and immunotherapy in the treatment of NSCLC. These findings highlight the potential of combining RFA, a localized treatment method, with immunotherapy, which acts systemically, to enhance the therapeutic outcomes of lung tumors in both preclinical and clinical settings.

MWA

MWA Combined with Immunotherapy in Preclinical Settings

Chimeric antigen receptor-modified T (CAR-T) cells have emerged as promising options for cancer treatment which has been verified by hematological malignancies; however, challenges remain for the application of CAR-T cells in solid tumors [92]. In a murine model with AXL-positive NSCLC patient-derived xenograft tumors, Cao et al. [93] discovered that combining MWA with AXL-CAR-T cells resulted in markedly enhanced antitumor efficacy without significant toxicities. The enhanced efficacy appeared to be associated with MWA’s capacity to facilitate the activation, infiltration, persistence, and tumor-suppressive properties of AXL-CAR T cells through the remodeling of the tumor microenvironment.

MWA Combined with Immunotherapy in Clinical Settings

Multiple studies have underscored the potential benefits of combining MWA with immunotherapy. Shao et al. [94] demonstrated a patient with advanced squamous lung cancer who had developed resistance to immunotherapy. After receiving MWA to ablate the primary lesion, the untreated metastatic lymph nodes also shrank obviously. Impressively, with a 6-month follow-up, there was no disease progression observed [94]. A patient with colorectal lung metastases has been successfully treated with multiple MWA followed by pembrolizumab, moreover, after an 8-month follow-up, no new or recurrent lung metastases were observed [95]. Yu et al. [96] conducted a randomized study involving 122 patients with NSCLC. Patients were divided into two groups: a control group receiving only anti-PD-1 monoclonal antibody and an observation group receiving MWA in combination with anti-PD-1 monoclonal antibody. The observation group reflected a superior RR and 1-, 2-, and 3-year survival rates (80.33%, 57.38%, 39.34%, and 29.51%) compared to the control group (62.30%, 32.79%, 18.03%, and 8.20%). Moreover, there was no significant difference in the incidence of complications between the two groups [96]. Wei and colleagues [97] prospectively enrolled 21 patients with advanced NSCLC who received sequential therapy of MWA and camrelizumab, an antibody targeting PD-1. The combined therapy was found to be safe, with an ORR of 33.3% which was superior to the previously reported ORR of camrelizumab treatment alone [97]. In a retrospective study, Huang et al. [98] evaluated 77 patients who underwent MWA followed by camrelizumab monotherapy or combined therapy. The results showed an ORR of 29.9%, a PFS of 11.8 months, and an OS that was not reached. Meanwhile, the incidence of adverse events was well tolerant, indicating that MWA combined with camrelizumab monotherapy or combined therapy (camrelizumab combined with chemotherapy, targeted therapy, or both) is a feasible option for patients with NSCLC [98].

Summarily, these studies emphasized the promising potential of combining MWA with immunotherapy, particularly PD-1/PD-L1 blockade, in the treatment of lung tumors, especially advanced NSCLC. The combination therapy appears to enhance treatment responses and potentially improve patient outcomes while maintaining a reasonable safety profile.

Cryoablation

Cryoablation Combined with Immunotherapy in Preclinical Settings

DCs play a critical role in antigen-presenting since they can identify antigens in their immature state and cross-present them in their mature state. CpG oligodeoxynucleotides (CpG-ODNs) are identified as immune adjuvants because they can bind to TLR9 that is expressed in both plasmacytoid DCs and myeloid DCs, further promoting antigen-specific humoral and cellular antitumor immunity [99]. Machlenkin et al. [100] found that the combined therapy of cryoablation and DCs enhanced tumor-specific CTL responses and improved prognosis in mice burdened with Lewis lung carcinoma. Additionally, in a preclinical Lewis lung carcinoma mice model, researchers found that the combination of cryoablation and intratumoral injection of immature DCs, along with immune adjuvant, CpG-ODNs, led to restricted tumor growth, reduced metastasis, and prolonged survival. What is more, the combined cryo-immunotherapy promoted the formation of antitumor memory, resulting in the protection of mice from rechallenge [101]. This favorable phenotype was attributed to tumor-specific type 1 T-cell responses, which are thought to stimulate the proliferation of CTLs and memory cells [101]. Zhang et al. [102] further investigated the optimal timing of CpG-ODN injection in the combined therapy strategies. They found that when cryoablation was performed before intratumoral DC injection, administering CpG-ODN 12 h after DC injection resulted in potent antitumor immunity responses, improved survival rates, and antimetastatic effects. This timing was superior to simultaneous delivery or administration at 6 h or 24 h after DC injection [102].

IL-12, a crucial antitumor cytokine, can be delivered into tumors via combination with viscous biopolymers, like chitosan solutions. Vrabel et al. [103] found that intratumoral injection of chitosan/IL-12 as a neoadjuvant immunotherapy in conjunction with cryoablation can reduce the number of metastatic lung nodules in comparison to cryoablation alone [103].

A nanovaccine combined with an immune adjuvant has been developed to capture immunogenic tumor antigens generated from cryoablation, which can further activate DCs and ultimately induce robust and enduring antitumor immunity. In mice bearing bilateral Lewis lung cancer tumors, cryoablation combined with nanovaccine demonstrated inhibition of primary tumors, regression of abscopal tumors, and improved survival rates [104]. Gu et al. [83] revealed that the combination of cryoablation with PD-1 blockade can restrain abscopal tumor growth in comparison with either treatment alone in mice bearing KP mutant lung cancer cells.

Cryoablation Combined with Immunotherapy in Clinical Settings

Adam et al. [105] reported a case in which cryoablation was applied to treat metastatic NSCLC that was resistant to checkpoint immunotherapy. The patient achieved a durable complete response, indicating the potential value of cryoablation in achieving local control of NSCLC patients with immunotherapy resistance [105]. Feng et al. [106] conducted a retrospective study involving 64 patients with advanced NSCLC. Two groups were compared: one treated with cryoablation and nivolumab, and the other treated with cryoablation alone. The combined therapy group demonstrated an elevation in immune function compared to the cryoablation-only group. Additionally, downregulation of circulating tumor cells and tumor markers were observed in the combined therapy group rather than in the cryoablation-only group. Moreover, at the 3-month follow-up, the disease control rates (DCRs) in the combined therapy group were superior to that in the cryoablation group (87.5% vs. 62.5%) [106]. Meng et al. [107] combined cryoablation with pembrolizumab in a patient with lung metastases from ovarian cancer, which led to the complete elimination of untreated pulmonary metastases. Gu et al. [83] demonstrated that combination therapy with cryoablation and PD-1 blockade induced significant tumor suppression and CD8+ T-cell infiltration in patients with unresectable NSCLC.

NK cells are a significant component of the innate immune system which plays a significant role in antitumor immunity, and adoptive NK cell transfer has been utilized in diverse cancer treatments [108, 109]. Lin et al. [109] enrolled 60 patients with NSCLC and divided them into two groups: one received cryoablation alone and the other received cryoablation combined with allogenic NK cell immunotherapy. The combined therapy group exhibited an elevated frequency and function of lymphocytes, especially NK cells, and demonstrated improved RRs and DCR at the 3-month follow-up compared to cryoablation alone (RR: 63.3% vs. 43.3%, DCR: 83.3% vs. 0.0%) [109].

DC-cytokine-induced killer cell therapy, a non-MHC-dependent cellular therapy, has been identified as an efficient immunotherapy for cancer [110]. Retrospective research involving 161 patients with metastatic NSCLC has been conducted by Yuanying et al. [111] to assess the efficacy of combination therapy of cryoablation, chemotherapy, and DC-cytokine-induced killer cell immunotherapy. Combining cryoablation with either chemotherapy or immunotherapy demonstrated prolonged OS (18 months and 17 months, respectively) compared with chemotherapy and chemo-immunotherapy (8.5 months and 12 months, respectively). Moreover, patients who received cryo-chemo-immunotherapy exhibited significantly extended survival (27 months) in comparison with patients who underwent other treatments [111].

In conclusion, research has revealed that the combination of thermal ablation with immunotherapy, which stimulates antitumor immunity, can effectively restrain the growth of primary tumors, suppress metastases, and improve survival outcomes in both preclinical (shown in Table 2) and clinical settings (shown in Table 3) for lung tumors. What is more, few cases have even demonstrated the potential value of applying thermal ablation in lung cancer patients who have developed resistance to anti-PD-1 therapy. However, the number of published articles regarding the combined therapy of thermal ablation and immunotherapy in lung tumors is limited, and there is a need for clinical trials with larger scales and longer follow-up times. Fortunately, more clinical trials are underway to explore the combination of thermal ablation and immunotherapy in lung tumors (shown in Table 4).

Table 2.

Combined therapy of thermal ablation and immunotherapy in animals with lung tumors

Author, yearAblation typeImmune therapyOutcomeSpeciesTumor typesGroup
Hamamoto et al. [85] (2013) RFA OK-432 Survival was significantly prolonged in the combination therapy group when compared with the other three groups. SGR in the combination therapy group became significantly smaller than those in the other three groups. Rabbit Lung and auricle tumors Control, RFA-only, OK-423 only, and RFA combined with local injection of OK-423 
Hamamoto et al. [87] (2015) RFA BCG Survival was significantly prolonged in the RFA-only and RFA/BCG groups compared with the control, but no significant difference was found between the RFA-only and RFA/BCG groups. SGR in the RFA/BCG group was significantly lower than in the control group, with no significant difference between the control and RFA-only groups. Rabbit Lung and auricle tumors Control, RFA-only, and RFA combined with local injection of BCG 
Xu et al. [88] (2019) RFA TLR9 agonist, CpG The combination of RFA and CpG treatment significantly reduced lung tumor metastases compared to the RFA treatment alone. Murine Lung tumor metastasis RFA-only, and RFA combined with local injection of CpG 
Li et al. [90] (2021) RFA MLT In terms of the non-ablated tumors, their growth was significantly inhibited after combined treatment of RFA and MLT when compared to tumors in the other three groups. Murine LLC Control, RFA-only, MLT only, and RFA combined with MLT 
Cao et al. [93] (2022) MWA AXL-CAR-T cells Compared with monotherapy, MWA combined with AXL-CAR-T cells exhibited superior local and systemic cell-derived xenografts tumor regression under a good safety threshold in NSG mice. Murine AXL-positive NSCLC patient-derived xenograft tumors Mock (PBS), CD19-CAR-T cells, AXL-CAR-T cells, MWA, MWA combined with CD19-CAR-T cells, and MWA combined with AXL-CAR-T cells 
Machlenkin et al. [100] (2005) Cryoablation Immature DCs Cryo-immunotherapy caused robust and tumor-specific CTL responses, increased Th1 responses, significantly prolonged survival, and dramatically reduced lung metastasis. Although intratumor administration of DCs alone increased the proliferation rate of CD8+ cells, only cryo-immunotherapy resulted in the generation of effector memory cells. Murine LLC Control, cryoablation-only, DC i.t., DC i.v., cryoablation combined with DC i.t., and cryoablation combined with DC i.v. 
Alteber et al. [101] (2014) Cryoablation Immature DCs and CpG-ODN Cryo-immunotherapy resulted in reduced tumor growth, low metastasis, and significantly prolonged survival. Moreover, this treatment induced antitumor memory that protected mice from tumor rechallenge. Murine LLC PBS, DC, CpG, DC combined with CpG, cryoablation combined with PBS, cryoablation combined with DC, cryoablation combined with CpG, and cryoablation combined with CpG and DC 
Zhang et al. [102] (2016) Cryoablation Immature DCs and CpG-ODN Higher ratios of CD4+ and CD8+ T cells and higher levels of IL-12, IFN-γ, and TNF-α were found in the blood of the mice that received CpG-ODN therapy 12 h after DC injection. In comparison with other groups, mice treated with CpG-ODN 12 h after DC exhibited better resistance to tumor rechallenge, demonstrating improved survival rates and antimetastatic effects. Murine LLC Cryoablation combined with DC and CpG (0 h), cryoablation combined with DC and CpG (6 h), cryoablation combined with DC and CpG (12 h), and cryoablation combined with DC and CpG (24 h) 
Vrabel et al. [103] (2023) Cryoablation CS/IL-12 The neoadjuvant addition of CS/IL-12 to cryoablation dramatically reduced the number of metastatic lung nodules compared to CA alone. Murine Spontaneously metastatic LLC1 Cryoablation alone, and cryoablation combined with CS/IL-12 
Yu et al. [104] (2023) Cryoablation Nanovaccine combined with an immune adjuvant In the bilateral Lewis lung cancer tumor model, AMNP-mediated cryoablation can significantly regress primary tumors, inhibit untreated abscopal tumor growth, and ultimately improve the long-term survival rate. Murine LLC Saline, AMNPs combined with cryoablation, MNPs combined with cryoablation, APS combined with cryoablation, cryoablation, AMNPs, MNPS, and APS 
Gu et al. [83] (2024) Cryoablation PD-1 antibody The combination of cryoablation with PD-1 blockade can restrain abscopal tumor growth in comparison with either treatment. Murine KP mutant lung cancer Control, cryoablation, anti-PD-1, combination of cryoablation and anti-PD-1 
Author, yearAblation typeImmune therapyOutcomeSpeciesTumor typesGroup
Hamamoto et al. [85] (2013) RFA OK-432 Survival was significantly prolonged in the combination therapy group when compared with the other three groups. SGR in the combination therapy group became significantly smaller than those in the other three groups. Rabbit Lung and auricle tumors Control, RFA-only, OK-423 only, and RFA combined with local injection of OK-423 
Hamamoto et al. [87] (2015) RFA BCG Survival was significantly prolonged in the RFA-only and RFA/BCG groups compared with the control, but no significant difference was found between the RFA-only and RFA/BCG groups. SGR in the RFA/BCG group was significantly lower than in the control group, with no significant difference between the control and RFA-only groups. Rabbit Lung and auricle tumors Control, RFA-only, and RFA combined with local injection of BCG 
Xu et al. [88] (2019) RFA TLR9 agonist, CpG The combination of RFA and CpG treatment significantly reduced lung tumor metastases compared to the RFA treatment alone. Murine Lung tumor metastasis RFA-only, and RFA combined with local injection of CpG 
Li et al. [90] (2021) RFA MLT In terms of the non-ablated tumors, their growth was significantly inhibited after combined treatment of RFA and MLT when compared to tumors in the other three groups. Murine LLC Control, RFA-only, MLT only, and RFA combined with MLT 
Cao et al. [93] (2022) MWA AXL-CAR-T cells Compared with monotherapy, MWA combined with AXL-CAR-T cells exhibited superior local and systemic cell-derived xenografts tumor regression under a good safety threshold in NSG mice. Murine AXL-positive NSCLC patient-derived xenograft tumors Mock (PBS), CD19-CAR-T cells, AXL-CAR-T cells, MWA, MWA combined with CD19-CAR-T cells, and MWA combined with AXL-CAR-T cells 
Machlenkin et al. [100] (2005) Cryoablation Immature DCs Cryo-immunotherapy caused robust and tumor-specific CTL responses, increased Th1 responses, significantly prolonged survival, and dramatically reduced lung metastasis. Although intratumor administration of DCs alone increased the proliferation rate of CD8+ cells, only cryo-immunotherapy resulted in the generation of effector memory cells. Murine LLC Control, cryoablation-only, DC i.t., DC i.v., cryoablation combined with DC i.t., and cryoablation combined with DC i.v. 
Alteber et al. [101] (2014) Cryoablation Immature DCs and CpG-ODN Cryo-immunotherapy resulted in reduced tumor growth, low metastasis, and significantly prolonged survival. Moreover, this treatment induced antitumor memory that protected mice from tumor rechallenge. Murine LLC PBS, DC, CpG, DC combined with CpG, cryoablation combined with PBS, cryoablation combined with DC, cryoablation combined with CpG, and cryoablation combined with CpG and DC 
Zhang et al. [102] (2016) Cryoablation Immature DCs and CpG-ODN Higher ratios of CD4+ and CD8+ T cells and higher levels of IL-12, IFN-γ, and TNF-α were found in the blood of the mice that received CpG-ODN therapy 12 h after DC injection. In comparison with other groups, mice treated with CpG-ODN 12 h after DC exhibited better resistance to tumor rechallenge, demonstrating improved survival rates and antimetastatic effects. Murine LLC Cryoablation combined with DC and CpG (0 h), cryoablation combined with DC and CpG (6 h), cryoablation combined with DC and CpG (12 h), and cryoablation combined with DC and CpG (24 h) 
Vrabel et al. [103] (2023) Cryoablation CS/IL-12 The neoadjuvant addition of CS/IL-12 to cryoablation dramatically reduced the number of metastatic lung nodules compared to CA alone. Murine Spontaneously metastatic LLC1 Cryoablation alone, and cryoablation combined with CS/IL-12 
Yu et al. [104] (2023) Cryoablation Nanovaccine combined with an immune adjuvant In the bilateral Lewis lung cancer tumor model, AMNP-mediated cryoablation can significantly regress primary tumors, inhibit untreated abscopal tumor growth, and ultimately improve the long-term survival rate. Murine LLC Saline, AMNPs combined with cryoablation, MNPs combined with cryoablation, APS combined with cryoablation, cryoablation, AMNPs, MNPS, and APS 
Gu et al. [83] (2024) Cryoablation PD-1 antibody The combination of cryoablation with PD-1 blockade can restrain abscopal tumor growth in comparison with either treatment. Murine KP mutant lung cancer Control, cryoablation, anti-PD-1, combination of cryoablation and anti-PD-1 

RFA, radiofrequency ablation; SGR, specific growth rate; BCG, bacillus Calmette-Guérin; TLR9, Toll-like receptor 9; MLT, melatonin; MWA, microwave ablation; CAR-T, chimeric antigen receptor-modified T; DC, dendritic cell; CTL, cytotoxic T lymphocyte; i.t., intratumor injection; i.v., intravenous injection; CS/IL-12, chitosan/interleukin-12; CA, cryoablation; LLC, Lewis lung cancer; KP, KrasG12D/+, Tp53−/−.

Table 3.

Combined therapy of thermal ablation and immunotherapy in patients with lung tumors

Author, yearAblation typeImmune therapyOutcomeSample sizeTumor typesStudy design
Yin et al. [91] (2018) RFA Atezolizumab The patient exhibited a significant response to atezolizumab at the lesion previously treated with RFA, while the response was not significant at lesions without prior RFA treatment. Stage IV NSCLC Case report 
Li et al. [90] (2021) RFA MLT Compared to the control group that only underwent surgical treatment, patients who received combined therapy of RFA and MLT demonstrated lower recurrence rates, fewer complications, and decreased patient hospitalization costs and duration. 42 Early lung cancer patients with multiple GGNs RCT 
Bäcklund and Freedman [95] (2017) MWA Pembrolizumab After 8 months of follow-up, there have been no signs of new or recurrent lung metastases. The patient suffered from neurological symptoms and upcoming diffuse nonmalignant lesions in both lungs. Colorectal lung metastases Case report 
Wei et al. [97] (2019) MWA Camrelizumab The ORR was 33.3%, with 2 patients achieving complete response and 5 patients achieving partial response. The median PFS was 5.1 months. The technical success rate was 100%. No treatment-associated deaths were identified. Major complications, minor complications, and side effects of MWA were observed in 9, 8, and 14 patients, respectively. Grade 2 and 3 camrelizumab adverse events were identified in 8 and 3 patients, respectively. 21 Stage IIIB/IIIC: 3; Stage IV: 18 Prospective research 
Shao et al. [94] (2021) MWA Camrelizumab and apatinib The untreated enlarged 4R/7 lymph nodes shrank significantly and continued to decrease during follow-up, indicating an abscopal effect of local ablation. Upon follow-up time of 7 months, the patient had not shown any signs of disease progression and obtained a durable response. Stage IV NSCLC acquired resistance of immunotherapy Case report 
Yu et al. [96] (2022) MWA Nivolumab Compared to the control group, the observation group demonstrated a robust RR and enhanced immune response, with no significant difference in side effects observed between the two groups. The observation group had greater 1-, 2-, and 3-year survival rates than the control group. 122 Control: stage I: 16, stage II: 12, stage III: 13, and stage IV: 20. Observation: 13, stage I: 13, stage II: 9, stage III: 16, stage IV: 23. RCT 
Huang et al. [98] (2022) MWA Camrelizumab monotherapy or combination therapy (camrelizumab combined with chemotherapy, targeted therapy, or both) Technical success was achieved in all patients, and the technique efficacy was 97.4%. The ORR was 29.9%. The PFS was 11.8 months. No periprocedural deaths due to ablation were observed. Complications were observed in 33 patients. 77 Stage III: 17; stage IV: 60 NSCLC Retrospective research 
Yuanying et al. [111] (2013) Cryoablation DC-CIK therapy Combining cryoablation with either chemotherapy or immunotherapy demonstrated prolonged OS compared with chemotherapy and chemo-immunotherapy. Moreover, patients who received cryo-chemo-immunotherapy exhibited significantly extended survival in comparison with patients who underwent other treatments. 161 Metastatic NSCLC Retrospective research 
Lin et al. [109] (2017) Cryoablation Allogenic NK cells Allogenic NK cells combined with cryosurgical treatment for advanced NSCLC demonstrated a synergistic effect, which not only enhanced the immune function of patients, improved the quality of life, and significantly increased the RR and DCR compared to cryoablation group. 60 Stage III, stage IV NSCLC Prospective research 
Adam et al. [105] (2018) Cryoablation PD-L1 and CTLA-4 antibody therapy The cryoablation was performed on the aortocaval lymph node with complete response for at least 9 months with no additional oncologic therapy. Nodal metastasis in NSCLC with acquired resistance to immunotherapy Case report 
Feng et al. [106] (2021) Cryoablation Nivolumab All adverse effects were manageable and no significant difference was noted between the two groups. Patients in the cryo-nivolumab group had a significant improvement in immune function and short-term efficacy. The levels of CTCs and tumor markers CYFRA21-1 and NSE in the cryo-nivolumab group were reduced significantly. 64 Cryo-nivolumab group: stage IIIB: 11, stage IV: 21; nivolumab group: stage IIIB: 9, stage IV: 23 Retrospective research 
Meng et al. [107] (2022) Cryoablation Pembrolizumab After cryoablation of the patient’s most significant lesion, the combined use of pembrolizumab resulted in complete remission of multiple pulmonary metastases, saving the patient’s life. Lung metastases from ovarian clear cell carcinoma Case report 
Gu et al. [83] (2024) Cryoablation PD-1 antibody The combination therapy significantly restrained the tumor and promoted CD8+ T-cell infiltration in TME. Unresectable NSCLC 
Author, yearAblation typeImmune therapyOutcomeSample sizeTumor typesStudy design
Yin et al. [91] (2018) RFA Atezolizumab The patient exhibited a significant response to atezolizumab at the lesion previously treated with RFA, while the response was not significant at lesions without prior RFA treatment. Stage IV NSCLC Case report 
Li et al. [90] (2021) RFA MLT Compared to the control group that only underwent surgical treatment, patients who received combined therapy of RFA and MLT demonstrated lower recurrence rates, fewer complications, and decreased patient hospitalization costs and duration. 42 Early lung cancer patients with multiple GGNs RCT 
Bäcklund and Freedman [95] (2017) MWA Pembrolizumab After 8 months of follow-up, there have been no signs of new or recurrent lung metastases. The patient suffered from neurological symptoms and upcoming diffuse nonmalignant lesions in both lungs. Colorectal lung metastases Case report 
Wei et al. [97] (2019) MWA Camrelizumab The ORR was 33.3%, with 2 patients achieving complete response and 5 patients achieving partial response. The median PFS was 5.1 months. The technical success rate was 100%. No treatment-associated deaths were identified. Major complications, minor complications, and side effects of MWA were observed in 9, 8, and 14 patients, respectively. Grade 2 and 3 camrelizumab adverse events were identified in 8 and 3 patients, respectively. 21 Stage IIIB/IIIC: 3; Stage IV: 18 Prospective research 
Shao et al. [94] (2021) MWA Camrelizumab and apatinib The untreated enlarged 4R/7 lymph nodes shrank significantly and continued to decrease during follow-up, indicating an abscopal effect of local ablation. Upon follow-up time of 7 months, the patient had not shown any signs of disease progression and obtained a durable response. Stage IV NSCLC acquired resistance of immunotherapy Case report 
Yu et al. [96] (2022) MWA Nivolumab Compared to the control group, the observation group demonstrated a robust RR and enhanced immune response, with no significant difference in side effects observed between the two groups. The observation group had greater 1-, 2-, and 3-year survival rates than the control group. 122 Control: stage I: 16, stage II: 12, stage III: 13, and stage IV: 20. Observation: 13, stage I: 13, stage II: 9, stage III: 16, stage IV: 23. RCT 
Huang et al. [98] (2022) MWA Camrelizumab monotherapy or combination therapy (camrelizumab combined with chemotherapy, targeted therapy, or both) Technical success was achieved in all patients, and the technique efficacy was 97.4%. The ORR was 29.9%. The PFS was 11.8 months. No periprocedural deaths due to ablation were observed. Complications were observed in 33 patients. 77 Stage III: 17; stage IV: 60 NSCLC Retrospective research 
Yuanying et al. [111] (2013) Cryoablation DC-CIK therapy Combining cryoablation with either chemotherapy or immunotherapy demonstrated prolonged OS compared with chemotherapy and chemo-immunotherapy. Moreover, patients who received cryo-chemo-immunotherapy exhibited significantly extended survival in comparison with patients who underwent other treatments. 161 Metastatic NSCLC Retrospective research 
Lin et al. [109] (2017) Cryoablation Allogenic NK cells Allogenic NK cells combined with cryosurgical treatment for advanced NSCLC demonstrated a synergistic effect, which not only enhanced the immune function of patients, improved the quality of life, and significantly increased the RR and DCR compared to cryoablation group. 60 Stage III, stage IV NSCLC Prospective research 
Adam et al. [105] (2018) Cryoablation PD-L1 and CTLA-4 antibody therapy The cryoablation was performed on the aortocaval lymph node with complete response for at least 9 months with no additional oncologic therapy. Nodal metastasis in NSCLC with acquired resistance to immunotherapy Case report 
Feng et al. [106] (2021) Cryoablation Nivolumab All adverse effects were manageable and no significant difference was noted between the two groups. Patients in the cryo-nivolumab group had a significant improvement in immune function and short-term efficacy. The levels of CTCs and tumor markers CYFRA21-1 and NSE in the cryo-nivolumab group were reduced significantly. 64 Cryo-nivolumab group: stage IIIB: 11, stage IV: 21; nivolumab group: stage IIIB: 9, stage IV: 23 Retrospective research 
Meng et al. [107] (2022) Cryoablation Pembrolizumab After cryoablation of the patient’s most significant lesion, the combined use of pembrolizumab resulted in complete remission of multiple pulmonary metastases, saving the patient’s life. Lung metastases from ovarian clear cell carcinoma Case report 
Gu et al. [83] (2024) Cryoablation PD-1 antibody The combination therapy significantly restrained the tumor and promoted CD8+ T-cell infiltration in TME. Unresectable NSCLC 

RFA, radiofrequency ablation; NSCLC, non-small cell lung cancer; MLT, melatonin; GGN, ground-glass nodule; RCT, randomized controlled trial; MWA, microwave ablation; ORR, objective response rate; PFS, progression-free survival; DC-CIK, dendritic cell-cytokine-induced killer cells; OS, overall survival; NK, nature killer; CTC, circulating tumor cell; CYFRA21-1, cytokeratin 21-1; NSE, neuron-specific enolase; TME, tumor microenvironment.

Table 4.

Administrated clinical trial regarding combined therapy of thermal ablation and immunotherapy in patients with lung tumors

StudyStudy designStudy participantsStudy purposeAblation typeImmune therapy
NCT05688280 Phase 1, phase 2 Metastatic solid tumor, colon cancer, NSCLC, soft tissue sarcoma Determine the safety and efficacy of IP-001 for intratumoral injection administration following thermal ablation of solid tumors. RFA IP-001 
NCT02469701 Phase 2 Advanced NSCLC Determine if the combination of nivolumab and ablation has higher systemic activity than previously reported with nivolumab alone. Ablation Nivolumab 
NCT04888806 Phase 2, single-arm Colorectal cancer liver metastasis or pulmonary metastasis Evaluate the effectiveness and safety of camrelizumab combined with MWA and chemotherapy in the treatment of colorectal cancer liver metastasis/pulmonary metastasis. MWA Camrelizumab combined with standard chemotherapy for mCRC 
NCT03769129 RCT Patients with stage IIIB–IV NSCLC who failed with first-line therapy Evaluate the safety and efficacy of pembrolizumab combined with MWA for patients with stage IIIB–IV NSCLC who failed with first-line therapy. MWA Pembrolizumab 
NCT04360655 RCT Advanced central NSCLC Evaluate the efficacy and safety of the first-line treatment in advanced central NSCLC patients by anti-PD-1/PD-L1 monoclonal antibody and chemotherapy versus anti-PD-1/PD-L1 monoclonal antibody and chemotherapy combined with bronchoscopic MWA. MWA Anti-PD-1/PD-L1 monoclonal antibody and chemotherapy 
NCT05053802 Phase 2 Multiple primary lung cancer Evaluate the efficiency and safety of MWA plus immune checkpoint inhibitor for patients with multiple primary lung cancer. MWA Camrelizumab 
NCT04102982 RCT Metastatic NSCLC Compare the efficacy and safety of camrelizumab alone verse combination of camrelizumab and MWA. MWA Camrelizumab 
NCT05532527 Single-arm Advanced NSCLC Evaluate the efficacy and safety of MWA combined with camrelizumab and chemotherapy in the treatment of patients with advanced NSCLC. MWA Camrelizumab and chemotherapy 
ChiCTR2000036114 Phase 2, RCT IIIb–IV stage of drive genes negative NSCLC Evaluate the efficacy and safety of PD-1 inhibitor combined with cryoablation in the second-line treatment of driver gene-negative advanced NSCLC. Cryoablation PD-1 inhibitor 
ChiCTR2100052468 Phase 2, RCT Advanced NSCLC Evaluate the efficacy and safety of combination of cryoablation and camrelizumab with chemotherapy combined versus camrelizumab with chemotherapy alone. Cryoablation Camrelizumab and chemotherapy 
NCT04339218 Phase 3, RCT Metastatic lung adenocarcinoma Compare the 1-year survival benefit of the association of cryoablation-pembrolizumab-pemetrexed-carboplatin versus pembrolizumab-pemetrexed-carboplatin in metastatic lung adenocarcinoma patients. Cryoablation Pembrolizumab and pemetrexed-carboplatin 
NCT04201990 Phase 1, phase 2 Multiple primary lung cancer Observe the safety and therapeutic effect of cryoablation combined with PD-1 antibody immunotherapy and anti-angiogenesis therapy in multiple primary lung cancer patients. Cryoablation Camrelizumab and apatinib 
StudyStudy designStudy participantsStudy purposeAblation typeImmune therapy
NCT05688280 Phase 1, phase 2 Metastatic solid tumor, colon cancer, NSCLC, soft tissue sarcoma Determine the safety and efficacy of IP-001 for intratumoral injection administration following thermal ablation of solid tumors. RFA IP-001 
NCT02469701 Phase 2 Advanced NSCLC Determine if the combination of nivolumab and ablation has higher systemic activity than previously reported with nivolumab alone. Ablation Nivolumab 
NCT04888806 Phase 2, single-arm Colorectal cancer liver metastasis or pulmonary metastasis Evaluate the effectiveness and safety of camrelizumab combined with MWA and chemotherapy in the treatment of colorectal cancer liver metastasis/pulmonary metastasis. MWA Camrelizumab combined with standard chemotherapy for mCRC 
NCT03769129 RCT Patients with stage IIIB–IV NSCLC who failed with first-line therapy Evaluate the safety and efficacy of pembrolizumab combined with MWA for patients with stage IIIB–IV NSCLC who failed with first-line therapy. MWA Pembrolizumab 
NCT04360655 RCT Advanced central NSCLC Evaluate the efficacy and safety of the first-line treatment in advanced central NSCLC patients by anti-PD-1/PD-L1 monoclonal antibody and chemotherapy versus anti-PD-1/PD-L1 monoclonal antibody and chemotherapy combined with bronchoscopic MWA. MWA Anti-PD-1/PD-L1 monoclonal antibody and chemotherapy 
NCT05053802 Phase 2 Multiple primary lung cancer Evaluate the efficiency and safety of MWA plus immune checkpoint inhibitor for patients with multiple primary lung cancer. MWA Camrelizumab 
NCT04102982 RCT Metastatic NSCLC Compare the efficacy and safety of camrelizumab alone verse combination of camrelizumab and MWA. MWA Camrelizumab 
NCT05532527 Single-arm Advanced NSCLC Evaluate the efficacy and safety of MWA combined with camrelizumab and chemotherapy in the treatment of patients with advanced NSCLC. MWA Camrelizumab and chemotherapy 
ChiCTR2000036114 Phase 2, RCT IIIb–IV stage of drive genes negative NSCLC Evaluate the efficacy and safety of PD-1 inhibitor combined with cryoablation in the second-line treatment of driver gene-negative advanced NSCLC. Cryoablation PD-1 inhibitor 
ChiCTR2100052468 Phase 2, RCT Advanced NSCLC Evaluate the efficacy and safety of combination of cryoablation and camrelizumab with chemotherapy combined versus camrelizumab with chemotherapy alone. Cryoablation Camrelizumab and chemotherapy 
NCT04339218 Phase 3, RCT Metastatic lung adenocarcinoma Compare the 1-year survival benefit of the association of cryoablation-pembrolizumab-pemetrexed-carboplatin versus pembrolizumab-pemetrexed-carboplatin in metastatic lung adenocarcinoma patients. Cryoablation Pembrolizumab and pemetrexed-carboplatin 
NCT04201990 Phase 1, phase 2 Multiple primary lung cancer Observe the safety and therapeutic effect of cryoablation combined with PD-1 antibody immunotherapy and anti-angiogenesis therapy in multiple primary lung cancer patients. Cryoablation Camrelizumab and apatinib 

NSCLC, non-small cell lung cancer; RFA, radiofrequency ablation; MWA, microwave ablation; mCRC, metastatic colorectal cancer; RCT, randomized controlled trial; PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1.

The Optimal Sequence and Timing of Combined Therapy

Determining the optimal sequence and timing of combined therapy is critical for developing effective treatment strategies. Currently, most preclinical studies have explored combined therapy in two main approaches: sequential therapy involving ablation followed by immunotherapy or simultaneous therapy with both ablation and immunotherapy. However, Silvestrini et al. [112] found that initiating immunotherapy (TLR9 agonist and checkpoint blockade) before combining it with MWA could offer several advantages. This scheme could suppress macrophages and MDSCs while enhancing CD8+ T cells that produce IFN-γ. What is more, starting immunotherapy before combined therapy demonstrated enhanced efficacy, especially in cases with a high tumor burden [112]. Despite several clinical trials underway to investigate the safety and efficacy of combined therapy, there remains a lack of focus on determining the optimal sequence and timing of these treatments. Further research in this area is essential to establish guidelines that maximize the therapeutic benefits of combined thermal ablation and immunotherapy for patients with lung tumors.

Individualized Combined Therapy

With the development of biomedicine, personalized and precious therapy has become a growing trend in clinical medicine. However, several critical questions persist in the context of combined therapy involving thermal ablation and immunotherapy for cancer. Determining which modality of ablation therapy can boost the antitumor immunity responses most effectively in specific patients is a complex challenge. Similarly, pinpointing the optimal immunotherapy for distinct patient populations is a complex issue, given that various immunotherapies, such as CAR-T-cell therapy or checkpoint inhibitors, may exhibit varying efficacy for specific patient profiles. Recognizing the patients who derive the greatest benefits from the combined therapy of thermal ablation and immunotherapy rather than alternative combinations represents a critical hurdle. The selection process may rely on individual tumor characteristics, patients’ overall health, and some other factors. It is crucial to develop reliable biomarkers or predictive models to identify potential candidates for combined therapies. To address these questions, large-scale clinical trials involving diverse patient subgroups, including those with different stages of cancer and various treatment histories, are necessary. These trials may broaden our horizons regarding the combination of thermal ablation and immunotherapy and guide more precise and personalized treatment strategies for patients with cancer.

Incomplete Ablation

Strategies aimed at avoiding incomplete ablation or counteracting the potential oncogenic effects of incomplete ablation in combined therapy are of great significance. Incomplete ablation can accelerate local tumor progression, induce recurrence and metastasis of tumors, and restrict the efficacy of anti-PD-1 therapy partly through the infiltration of MDSCs which further induces a suppressive tumor microenvironment [113‒115]. Inhibitors targeting specific oncogenic pathways in incomplete ablation, such as CCL-2 [113], Circ-BANP [116], intercellular adhesion molecule 1 (ICAM-1) [117], or nuclear receptor subfamily 2, group F, member 6 (NR2F6) [118], can be considered in conjunction with immunotherapy. Some studies have evaluated the clinical outcome of repeated ablation after incomplete ablation. Repeated ablation is safe and relatively effective in managing residual tumors resulting from insufficient initial ablation [119]; however, the influence of repeated ablation on immunity is unclear, and whether it can be synergistic with immunotherapy remains largely unknown.

Further exploration regarding the combination of thermal ablation and immunotherapy is necessary which can not only help us identify the patient populations that would benefit the most but also help optimize treatment strategies to maximize the efficacy of combined therapy. Such trials are of great importance to improve the outcomes of patients with lung tumors.

Percutaneous thermal ablation, for instance, RFA, MWA, and cryoablation have been verified as effective and minimally invasive local therapies exhibiting substantial control over local tumors and improved survival rates for patients with lung tumors. With the development of technology, transbronchial ablation emerges as a promising treatment option for patients with lung tumors. It holds the potential for reduced invasiveness and lower complication rates when compared with percutaneous ablation. However, more studies are needed to verify its efficacy and safety.

Additionally, thermal ablation may alter the local immune microenvironment, transforming initially “cold” tumors into “hot” ones, thereby potentially exhibiting a synergistic effect with immunotherapy in terms of lung tumors. We believe that combining ablative therapy and immunotherapy will yield substantial clinical advantages for patients with lung tumors. Its application prospects are broad, potentially extending to the entire treatment cycle of lung tumors, including early-stage patients, advanced-stage patients, targeted drug-resistant patients, chemotherapy-resistant patients, and immunotherapy-resistant patients. However, in the field of lung tumors, research regarding the combination of thermal ablation and immunotherapy is still at an early stage. Several crucial questions remain mysteries including the methods for individualized treatment selection and the identification of the patient populations that would benefit most from specific combination therapy regimens. Meanwhile, inspired by the iSABR trial [17], as a local treatment modality like radiotherapy, the combination of thermal ablation and immunotherapy may also hold the potential to bring clinical benefits to patients with early-stage NSCLC. However, at present, most clinical studies investigating thermal ablation combined with immunotherapy focus on metastatic tumors or advanced lung tumors, and no studies are concentrating on patients with early-stage lung tumors. This represents a gap that needs to be addressed in the field of combination involving thermal ablation and immunotherapy. To address these questions, large-scale and high-quality trials are needed.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

This work was supported by National Multi-disciplinary Treatment Project for Major Diseases (2020NMDTP), Nurture projects for basic research of Shanghai Chest Hospital (2021YNJCQ4), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20181815).

Rui Yang and Chuanjia Gu were equally responsible for the conception of the manuscript, the collection of data, the writing of the draft manuscript, the drawing of figures, the summarizing of tables, and the critical revision of the manuscript. Fangfang Xie and Siyuan Hong reviewed, modified, and polished this manuscript. Jiayuan Sun and Felix J.F. Herth designed, supervised, reviewed, and revised this manuscript. All authors reviewed and approved the submission of the final manuscript.

Additional Information

Rui Yang and Chuanjia Gu contributed equally to this work.

All data come from published journal articles.

1.
Brody
H
.
Lung cancer
.
Nature
.
2020
;
587
(
7834
):
S7
.
2.
Leiter
A
,
Veluswamy
RR
,
Wisnivesky
JP
.
The global burden of lung cancer: current status and future trends
.
Nat Rev Clin Oncol
.
2023
;
20
(
9
):
624
39
.
3.
Tandberg
DJ
,
Tong
BC
,
Ackerson
BG
,
Kelsey
CR
.
Surgery versus stereotactic body radiation therapy for stage I non–small cell lung cancer: a comprehensive review
.
Cancer
.
2018
;
124
(
4
):
667
78
.
4.
Altorki
N
,
Wang
X
,
Kozono
D
,
Watt
C
,
Landrenau
R
,
Wigle
D
, et al
.
Lobar or sublobar resection for peripheral stage IA non-small-cell lung cancer
.
N Engl J Med
.
2023
;
388
(
6
):
489
98
.
5.
Daly
ME
,
Beagen
P
,
Madani
MH
.
Nonsurgical therapy for early-stage lung cancer
.
Hematol Oncol Clin North Am
.
2023
;
37
(
3
):
499
512
.
6.
Kennedy
LB
,
Salama
AKS
.
A review of cancer immunotherapy toxicity
.
CA Cancer J Clin
.
2020
;
70
(
2
):
86
104
.
7.
Zhang
Y
,
Zhang
Z
.
The history and advances in cancer immunotherapy: understanding the characteristics of tumor-infiltrating immune cells and their therapeutic implications
.
Cell Mol Immunol
.
2020
;
17
(
8
):
807
21
.
8.
Novello
S
,
Kowalski
DM
,
Luft
A
,
Gümüş
M
,
Vicente
D
,
Mazières
J
, et al
.
Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study
.
J Clin Oncol
.
2023
;
41
(
11
):
1999
2006
.
9.
Reck
M
,
Rodríguez-Abreu
D
,
Robinson
AG
,
Hui
R
,
Csőszi
T
,
Fülöp
A
, et al
.
Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50
.
J Clin Oncol
.
2021
;
39
(
21
):
2339
49
.
10.
de Castro
GJ
,
Kudaba
I
,
Wu
YL
,
Lopes
G
,
Kowalski
DM
,
Turna
HZ
, et al
.
Five-year outcomes with pembrolizumab versus chemotherapy as first-line therapy in patients with non-small-cell lung cancer and programmed death ligand-1 tumor proportion score ≥ 1% in the KEYNOTE-042 study
.
J Clin Oncol
.
2023
;
41
(
11
):
1986
91
.
11.
Garassino
MC
,
Gadgeel
S
,
Speranza
G
,
Felip
E
,
Esteban
E
,
Dómine
M
, et al
.
Pembrolizumab plus pemetrexed and platinum in nonsquamous non-small-cell lung cancer: 5-year outcomes from the phase 3 KEYNOTE-189 study
.
J Clin Oncol
.
2023
;
41
(
11
):
1992
8
.
12.
Brahmer
JR
,
Lee
JS
,
Ciuleanu
TE
,
Bernabe Caro
R
,
Nishio
M
,
Urban
L
, et al
.
Five-year survival outcomes with nivolumab plus ipilimumab versus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer in CheckMate 227
.
J Clin Oncol
.
2023
;
41
(
6
):
1200
12
.
13.
Zhu
S
,
Zhang
T
,
Zheng
L
,
Liu
H
,
Song
W
,
Liu
D
, et al
.
Combination strategies to maximize the benefits of cancer immunotherapy
.
J Hematol Oncol
.
2021
;
14
(
1
):
156
.
14.
Reck
M
,
Rodríguez-Abreu
D
,
Robinson
AG
,
Hui
R
,
Csőszi
T
,
Fülöp
A
, et al
.
Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer
.
N Engl J Med
.
2016
;
375
(
19
):
1823
33
.
15.
Herbst
RS
,
Giaccone
G
,
de Marinis
F
,
Reinmuth
N
,
Vergnenegre
A
,
Barrios
CH
, et al
.
Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC
.
N Engl J Med
.
2020
;
383
(
14
):
1328
39
.
16.
Sezer
A
,
Kilickap
S
,
Gümüş
M
,
Bondarenko
I
,
Özgüroğlu
M
,
Gogishvili
M
, et al
.
Cemiplimab monotherapy for first-line treatment of advanced non-small-cell lung cancer with PD-L1 of at least 50%: a multicentre, open-label, global, phase 3, randomised, controlled trial
.
Lancet
.
2021
;
397
(
10274
):
592
604
.
17.
Chang
JY
,
Lin
SH
,
Dong
W
,
Liao
Z
,
Gandhi
SJ
,
Gay
CM
, et al
.
Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial
.
Lancet
.
2023
;
402
(
10405
):
871
81
.
18.
Theelen
WSME
,
Chen
D
,
Verma
V
,
Hobbs
BP
,
Peulen
HMU
,
Aerts
JGJV
, et al
.
Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials
.
Lancet Respir Med
.
2021
;
9
(
5
):
467
75
.
19.
Theelen
WSME
,
Peulen
HMU
,
Lalezari
F
,
van der Noort
V
,
de Vries
JF
,
Aerts
JGJV
, et al
.
Effect of pembrolizumab after stereotactic body radiotherapy vs pembrolizumab alone on tumor response in patients with advanced non-small cell lung cancer: results of the PEMBRO-RT phase 2 randomized clinical trial
.
JAMA Oncol
.
2019
;
5
(
9
):
1276
82
.
20.
Park
HS
,
Detterbeck
FC
,
Madoff
DC
,
Bade
BC
,
Kumbasar
U
,
Mase
VJ
Jr
, et al
.
A guide for managing patients with stage I NSCLC: deciding between lobectomy, segmentectomy, wedge, SBRT and ablation-part 4: systematic review of evidence involving SBRT and ablation
.
J Thorac Dis
.
2022
;
14
(
6
):
2412
36
.
21.
Steinfort
DP
,
Herth
FJF
.
Bronchoscopic treatments for early-stage peripheral lung cancer: are we ready for prime time
.
Respirology
.
2020
;
25
(
9
):
944
52
.
22.
Chu
KF
,
Dupuy
DE
.
Thermal ablation of tumours: biological mechanisms and advances in therapy
.
Nat Rev Cancer
.
2014
;
14
(
3
):
199
208
.
23.
Bartlett
EC
,
Rahman
S
,
Ridge
CA
.
Percutaneous image-guided thermal ablation of lung cancer: what is the evidence
.
Lung Cancer
.
2023
;
176
:
14
23
.
24.
Han
X
,
Wang
R
,
Xu
J
,
Chen
Q
,
Liang
C
,
Chen
J
, et al
.
In situ thermal ablation of tumors in combination with nano-adjuvant and immune checkpoint blockade to inhibit cancer metastasis and recurrence
.
Biomaterials
.
2019
;
224
:
119490
.
25.
Venturini
M
,
Cariati
M
,
Marra
P
,
Masala
S
,
Pereira
PL
,
Carrafiello
G
.
CIRSE standards of practice on thermal ablation of primary and secondary lung tumours
.
Cardiovasc Intervent Radiol
.
2020
;
43
(
5
):
667
83
.
26.
Ye
X
,
Fan
W
,
Wang
H
,
Wang
J
,
Wang
Z
,
Gu
S
, et al
.
Expert consensus workshop report: guidelines for thermal ablation of primary and metastatic lung tumors (2018 edition)
.
J Cancer Res Ther
.
2018
;
14
(
4
):
730
44
.
27.
Liu
B
,
Liu
L
,
Hu
M
,
Qian
K
,
Li
Y
.
Percutaneous radiofrequency ablation for medically inoperable patients with clinical stage I non-small cell lung cancer
.
Thorac Cancer
.
2015
;
6
(
3
):
327
33
.
28.
Palussière
J
,
Chomy
F
,
Savina
M
,
Deschamps
F
,
Gaubert
JY
,
Renault
A
, et al
.
Radiofrequency ablation of stage IA non-small cell lung cancer in patients ineligible for surgery: results of a prospective multicenter phase II trial
.
J Cardiothorac Surg
.
2018
;
13
(
1
):
91
.
29.
Ambrogi
MC
,
Fanucchi
O
,
Cioni
R
,
Dini
P
,
De Liperi
A
,
Cappelli
C
, et al
.
Long-term results of radiofrequency ablation treatment of stage I non-small cell lung cancer: a prospective intention-to-treat study
.
J Thorac Oncol
.
2011
;
6
(
12
):
2044
51
.
30.
Yang
X
,
Ye
X
,
Zheng
A
,
Huang
G
,
Ni
X
,
Wang
J
, et al
.
Percutaneous microwave ablation of stage I medically inoperable non-small cell lung cancer: clinical evaluation of 47 cases
.
J Surg Oncol
.
2014
;
110
(
6
):
758
63
.
31.
Zhong
L
,
Sun
S
,
Shi
J
,
Cao
F
,
Han
X
,
Bao
X
, et al
.
Clinical analysis on 113 patients with lung cancer treated by percutaneous CT-guided microwave ablation
.
J Thorac Dis
.
2017
;
9
(
3
):
590
7
.
32.
Acksteiner
C
,
Steinke
K
.
Percutaneous microwave ablation for early-stage non-small cell lung cancer (NSCLC) in the elderly: a promising outlook
.
J Med Imaging Radiat Oncol
.
2015
;
59
(
1
):
82
90
.
33.
Han
X
,
Yang
X
,
Huang
G
,
Li
C
,
Zhang
L
,
Qiao
Y
, et al
.
Safety and clinical outcomes of computed tomography-guided percutaneous microwave ablation in patients aged 80 years and older with early-stage non-small cell lung cancer: a multicenter retrospective study
.
Thorac Cancer
.
2019
;
10
(
12
):
2236
42
.
34.
Yang
X
,
Ye
X
,
Lin
Z
,
Jin
Y
,
Zhang
K
,
Dong
Y
, et al
.
Computed tomography-guided percutaneous microwave ablation for treatment of peripheral ground-glass opacity-Lung adenocarcinoma: a pilot study
.
J Cancer Res Ther
.
2018
;
14
(
4
):
764
71
.
35.
Yamauchi
Y
,
Izumi
Y
,
Hashimoto
K
,
Yashiro
H
,
Inoue
M
,
Nakatsuka
S
, et al
.
Percutaneous cryoablation for the treatment of medically inoperable stage I non-small cell lung cancer
.
PLoS One
.
2012
;
7
(
3
):
e33223
.
36.
Moore
W
,
Talati
R
,
Bhattacharji
P
,
Bilfinger
T
.
Five-year survival after cryoablation of stage I non-small cell lung cancer in medically inoperable patients
.
J Vasc Interv Radiol
.
2015
;
26
(
3
):
312
9
.
37.
Liu
S
,
Zhu
X
,
Qin
Z
,
Xu
J
,
Zeng
J
,
Chen
J
, et al
.
Computed tomography-guided percutaneous cryoablation for lung ground-glass opacity: a pilot study
.
J Cancer Res Ther
.
2019
;
15
(
2
):
370
4
.
38.
de Baère
T
,
Aupérin
A
,
Deschamps
F
,
Chevallier
P
,
Gaubert
Y
,
Boige
V
, et al
.
Radiofrequency ablation is a valid treatment option for lung metastases: experience in 566 patients with 1037 metastases
.
Ann Oncol
.
2015
;
26
(
5
):
987
91
.
39.
Ghosn
M
,
Solomon
SB
.
Current management of oligometastatic lung cancer and future perspectives: results of thermal ablation as a local ablative therapy
.
Cancers
.
2021
;
13
(
20
):
5202
.
40.
Masuda
E
,
Sista
AK
,
Pua
BB
,
Madoff
DC
.
Palliative procedures in lung cancer
.
Semin Intervent Radiol
.
2013
;
30
(
2
):
199
205
.
41.
Chua
TC
,
Sarkar
A
,
Saxena
A
,
Glenn
D
,
Zhao
J
,
Morris
DL
.
Long-term outcome of image-guided percutaneous radiofrequency ablation of lung metastases: an open-labeled prospective trial of 148 patients
.
Ann Oncol
.
2010
;
21
(
10
):
2017
22
.
42.
Petre
EN
,
Jia
X
,
Thornton
RH
,
Sofocleous
CT
,
Alago
W
,
Kemeny
NE
, et al
.
Treatment of pulmonary colorectal metastases by radiofrequency ablation
.
Clin Colorectal Cancer
.
2013
;
12
(
1
):
37
44
.
43.
Pan
C
,
Wu
P
,
Yu
J
,
Li
W
,
Huang
Z
,
Wang
J
, et al
.
Comparative survival analysis in patients with pulmonary metastases from nasopharyngeal carcinoma treated with radiofrequency ablation
.
Eur J Radiol
.
2012
;
81
(
4
):
e473
477
.
44.
Li
X
,
Zhao
M
,
Wang
J
,
Fan
W
,
Li
W
,
Pan
T
, et al
.
Percutaneous CT-guided radiofrequency ablation as supplemental therapy after systemic chemotherapy for selected advanced non-small cell lung cancers
.
AJR Am J Roentgenol
.
2013
;
201
(
6
):
1362
7
.
45.
Qi
H
,
Wan
C
,
Li
X
,
Zhang
L
,
Song
Z
,
Fan
W
.
Computed tomography-guided percutaneous microwave ablation treatment for lung metastases from nasopharyngeal carcinoma
.
Indian J Cancer
.
2015
;
52
(
Suppl 2
):
e91
5
.
46.
Egashira
Y
,
Singh
S
,
Bandula
S
,
Illing
R
.
Percutaneous high-energy microwave ablation for the treatment of pulmonary tumors: a retrospective single-center experience
.
J Vasc Interv Radiol
.
2016
;
27
(
4
):
474
9
.
47.
de Baere
T
,
Tselikas
L
,
Woodrum
D
,
Abtin
F
,
Littrup
P
,
Deschamps
F
, et al
.
Evaluating cryoablation of metastatic lung tumors in patients--safety and efficacy: the ECLIPSE trial--interim analysis at 1 year
.
J Thorac Oncol
.
2015
;
10
(
10
):
1468
74
.
48.
Callstrom
MR
,
Woodrum
DA
,
Nichols
FC
,
Palussiere
J
,
Buy
X
,
Suh
RD
, et al
.
Multicenter study of metastatic lung tumors targeted by interventional cryoablation evaluation (SOLSTICE)
.
J Thorac Oncol
.
2020
;
15
(
7
):
1200
9
.
49.
de Baère
T
,
Woodrum
D
,
Tselikas
L
,
Abtin
F
,
Littrup
P
,
Deschamps
F
, et al
.
The ECLIPSE study: efficacy of cryoablation on metastatic lung tumors with a 5-year follow-up
.
J Thorac Oncol
.
2021
;
16
(
11
):
1840
9
.
50.
Gao
W
,
Guo
Z
,
Shu
S
,
Xing
W
,
Zhang
W
,
Yang
X
.
The application effect of percutaneous cryoablation for the stage IIIB/IV advanced non-small-cell lung cancer after the failure of chemoradiotherapy
.
Asian J Surg
.
2018
;
41
(
6
):
530
6
.
51.
Pereira
PL
,
Masala
S
;
Cardiovascular and Interventional Radiological Society of Europe CIRSE
.
Standards of practice: guidelines for thermal ablation of primary and secondary lung tumors
.
Cardiovasc Intervent Radiol
.
2012
;
35
(
2
):
247
54
.
52.
Alexander
ES
,
Dupuy
DE
.
Lung cancer ablation: technologies and techniques
.
Semin Intervent Radiol
.
2013
;
30
(
2
):
141
50
.
53.
Najafi
A
,
Baere
T
,
Madani
K
,
Al-Ahmar
M
,
Roux
C
,
Delpla
A
, et al
.
Lung ablation - how I do it
.
Tech Vasc Interv Radiol
.
2020
;
23
(
2
):
100673
.
54.
Lin
M
,
Eiken
P
,
Blackmon
S
.
Image guided thermal ablation in lung cancer treatment
.
J Thorac Dis
.
2020
;
12
(
11
):
7039
47
.
55.
de Baere
T
,
Tselikas
L
,
Catena
V
,
Buy
X
,
Deschamps
F
,
Palussière
J
.
Percutaneous thermal ablation of primary lung cancer
.
Diagn Interv Imaging
.
2016
;
97
(
10
):
1019
24
.
56.
Lubner
MG
,
Brace
CL
,
Hinshaw
JL
,
Lee
FT
.
Microwave tumor ablation: mechanism of action, clinical results, and devices
.
J Vasc Interv Radiol
.
2010
;
21
(
8 Suppl
):
S192
203
.
57.
Brace
CL
,
Laeseke
PF
,
Sampson
LA
,
Frey
TM
,
van der Weide
DW
,
Lee
FT
Jr
.
Microwave ablation with a single small-gauge triaxial antenna: in vivo porcine liver model
.
Radiology
.
2007
;
242
(
2
):
435
40
.
58.
Allaf
ME
,
Varkarakis
IM
,
Bhayani
SB
,
Inagaki
T
,
Kavoussi
LR
,
Solomon
SB
.
Pain control requirements for percutaneous ablation of renal tumors: cryoablation versus radiofrequency ablation--initial observations
.
Radiology
.
2005
;
237
(
1
):
366
70
.
59.
Thacker
PG
,
Callstrom
MR
,
Curry
TB
,
Mandrekar
JN
,
Atwell
TD
,
Goetz
MP
, et al
.
Palliation of painful metastatic disease involving bone with imaging-guided treatment: comparison of patients’ immediate response to radiofrequency ablation and cryoablation
.
AJR Am J Roentgenol
.
2011
;
197
(
2
):
510
5
.
60.
Steinfort
DP
,
Antippa
P
,
Rangamuwa
K
,
Irving
LB
,
Christie
M
,
Chan
E
, et al
.
Safety and feasibility of a novel externally cooled bronchoscopic radiofrequency ablation catheter for ablation of peripheral lung tumours: a first-in-human dose escalation study
.
Respiration
.
2023
;
102
(
3
):
211
9
.
61.
Xie
F
,
Zheng
X
,
Xiao
B
,
Han
B
,
Herth
FJF
,
Sun
J
.
Navigation bronchoscopy-guided radiofrequency ablation for nonsurgical peripheral pulmonary tumors
.
Respiration
.
2017
;
94
(
3
):
293
8
.
62.
Xie
F
,
Chen
J
,
Jiang
Y
,
Sun
J
,
Hogarth
DK
,
Herth
FJF
.
Microwave ablation via a flexible catheter for the treatment of nonsurgical peripheral lung cancer: a pilot study
.
Thorac Cancer
.
2022
;
13
(
7
):
1014
20
.
63.
Gu
C
,
Yuan
H
,
Yang
C
,
Xie
F
,
Chen
J
,
Zhu
L
, et al
.
Transbronchial cryoablation in peripheral lung parenchyma with a novel thin cryoprobe and initial clinical testing
.
Thorax
.
2024
:
thorax-2023-220227
.
64.
Sabath
BF
,
Casal
RF
.
Bronchoscopic ablation of peripheral lung tumors
.
J Thorac Dis
.
2019
;
11
(
6
):
2628
38
.
65.
Tanabe
T
,
Koizumi
T
,
Tsushima
K
,
Ito
M
,
Kanda
S
,
Kobayashi
T
, et al
.
Comparative study of three different catheters for CT imaging-bronchoscopy-guided radiofrequency ablation as a potential and novel interventional therapy for lung cancer
.
Chest
.
2010
;
137
(
4
):
890
7
.
66.
Pritchett
MA
,
Schampaert
S
,
de Groot
JAH
,
Schirmer
CC
,
van der Bom
I
.
Cone-beam CT with augmented fluoroscopy combined with electromagnetic navigation bronchoscopy for biopsy of pulmonary nodules
.
J Bronchology Interv Pulmonol
.
2018
;
25
(
4
):
274
82
.
67.
Herth
FJ
,
Eberhardt
R
,
Sterman
D
,
Silvestri
GA
,
Hoffmann
H
,
Shah
PL
.
Bronchoscopic transparenchymal nodule access (BTPNA): first in human trial of a novel procedure for sampling solitary pulmonary nodules
.
Thorax
.
2015
;
70
(
4
):
326
32
.
68.
Todorova
VK
,
Klimberg
VS
,
Hennings
L
,
Kieber-Emmons
T
,
Pashov
A
.
Immunomodulatory effects of radiofrequency ablation in a breast cancer model
.
Immunol Invest
.
2010
;
39
(
1
):
74
92
.
69.
Fietta
AM
,
Morosini
M
,
Passadore
I
,
Cascina
A
,
Draghi
P
,
Dore
R
, et al
.
Systemic inflammatory response and downmodulation of peripheral CD25+Foxp3+ T-regulatory cells in patients undergoing radiofrequency thermal ablation for lung cancer
.
Hum Immunol
.
2009
;
70
(
7
):
477
86
.
70.
Schneider
T
,
Sevko
A
,
Heussel
CP
,
Umansky
L
,
Beckhove
P
,
Dienemann
H
, et al
.
Serum inflammatory factors and circulating immunosuppressive cells are predictive markers for efficacy of radiofrequency ablation in non-small-cell lung cancer
.
Clin Exp Immunol
.
2015
;
180
(
3
):
467
74
.
71.
Shaobin
W
,
Yu
X
,
Jiatian
L
,
Zaizhong
C
,
Luping
D
,
Junhui
C
.
Changes of CD4+ T-cell subsets after radiofrequency ablation in lung cancer and its significance
.
J Cancer Res Ther
.
2016
;
12
(
Supplement
):
C166
70
.
72.
Schneider
T
,
Hoffmann
H
,
Dienemann
H
,
Herpel
E
,
Heussel
CP
,
Enk
AH
, et al
.
Immune response after radiofrequency ablation and surgical resection in nonsmall cell lung cancer
.
Semin Thorac Cardiovasc Surg
.
2016
;
28
(
2
):
585
92
.
73.
Haen
SP
,
Gouttefangeas
C
,
Schmidt
D
,
Boss
A
,
Clasen
S
,
von Herbay
A
, et al
.
Elevated serum levels of heat shock protein 70 can be detected after radiofrequency ablation
.
Cell Stress Chaperones
.
2011
;
16
(
5
):
495
504
.
74.
Zhang
L
,
Zhang
M
,
Wang
J
,
Li
Y
,
Wang
T
,
Xia
J
, et al
.
Immunogenic change after percutaneous microwave ablation in pulmonary malignancies: variation in immune cell subsets and cytokines in peripheral blood
.
Front Immunol
.
2022
;
13
:
1069192
.
75.
Xu
H
,
Tan
X
,
Kong
Y
,
Huang
Y
,
Wei
Z
,
Ye
X
.
Microwave ablation of non-small cell lung cancer tumors changes plasma levels of cytokines IL-2 and IFN-γ
.
J Cancer Res Ther
.
2022
;
18
(
2
):
532
44
.
76.
Xu
H
,
Sun
W
,
Kong
Y
,
Huang
Y
,
Wei
Z
,
Zhang
L
, et al
.
Immune abscopal effect of microwave ablation for lung metastases of endometrial carcinoma
.
J Cancer Res Ther
.
2020
;
16
(
7
):
1718
21
.
77.
Aarts
BM
,
Klompenhouwer
EG
,
Rice
SL
,
Imani
F
,
Baetens
T
,
Bex
A
, et al
.
Cryoablation and immunotherapy: an overview of evidence on its synergy
.
Insights Imaging
.
2019
;
10
(
1
):
53
.
78.
Jansen
MC
,
van Hillegersberg
R
,
Schoots
IG
,
Levi
M
,
Beek
JF
,
Crezee
H
, et al
.
Cryoablation induces greater inflammatory and coagulative responses than radiofrequency ablation or laser induced thermotherapy in a rat liver model
.
Surgery
.
2010
;
147
(
5
):
686
95
.
79.
Chapman
WC
,
Debelak
JP
,
Wright Pinson
C
,
Washington
MK
,
Atkinson
JB
,
Venkatakrishnan
A
, et al
.
Hepatic cryoablation, but not radiofrequency ablation, results in lung inflammation
.
Ann Surg
.
2000
;
231
(
5
):
752
61
.
80.
Sabel
MS
,
Su
G
,
Griffith
KA
,
Chang
AE
.
Rate of freeze alters the immunologic response after cryoablation of breast cancer
.
Ann Surg Oncol
.
2010
;
17
(
4
):
1187
93
.
81.
Takahashi
Y
,
Izumi
Y
,
Matsutani
N
,
Dejima
H
,
Nakayama
T
,
Okamura
R
, et al
.
Optimized magnitude of cryosurgery facilitating anti-tumor immunoreaction in a mouse model of Lewis lung cancer
.
Cancer Immunol Immunother
.
2016
;
65
(
8
):
973
82
.
82.
Yang
X
,
Guo
Y
,
Guo
Z
,
Si
T
,
Xing
W
,
Yu
W
, et al
.
Cryoablation inhibition of distant untreated tumors (abscopal effect) is immune mediated
.
Oncotarget
.
2019
;
10
(
41
):
4180
91
.
83.
Gu
C
,
Wang
X
,
Wang
K
,
Xie
F
,
Chen
L
,
Ji
H
, et al
.
Cryoablation triggers type I interferon-dependent antitumor immunity and potentiates immunotherapy efficacy in lung cancer
.
J Immunother Cancer
.
2024
;
12
(
1
):
e008386
.
84.
Li
L
,
Wang
W
,
Pan
H
,
Ma
G
,
Shi
X
,
Xie
H
, et al
.
Microwave ablation combined with OK-432 induces Th1-type response and specific antitumor immunity in a murine model of breast cancer
.
J Transl Med
.
2017
;
15
(
1
):
23
.
85.
Hamamoto
S
,
Okuma
T
,
Yamamoto
A
,
Kageyama
K
,
Takeshita
T
,
Sakai
Y
, et al
.
Radiofrequency ablation and immunostimulant OK-432: combination therapy enhances systemic antitumor immunity for treatment of VX2 lung tumors in rabbits
.
Radiology
.
2013
;
267
(
2
):
405
13
.
86.
Lange
C
,
Aaby
P
,
Behr
MA
,
Donald
PR
,
Kaufmann
SHE
,
Netea
MG
, et al
.
100 years of Mycobacterium bovis bacille Calmette-Guérin
.
Lancet Infect Dis
.
2022
;
22
(
1
):
e2
12
.
87.
Hamamoto
S
,
Okuma
T
,
Yamamoto
A
,
Kageyama
K
,
Ueki
A
,
Matsuoka
T
, et al
.
Combination radiofrequency ablation and local injection of the immunostimulant bacillus Calmette-Guérin induces antitumor immunity in the lung and at a distant VX2 tumor in a rabbit model
.
J Vasc Interv Radiol
.
2015
;
26
(
2
):
271
8
.
88.
Xu
A
,
Zhang
L
,
Yuan
J
,
Babikr
F
,
Freywald
A
,
Chibbar
R
, et al
.
TLR9 agonist enhances radiofrequency ablation-induced CTL responses, leading to the potent inhibition of primary tumor growth and lung metastasis
.
Cel Mol Immunol
.
2019
;
16
(
10
):
820
32
.
89.
Kou
J
,
Liu
J
,
Gu
X
,
Liu
N
.
The efficacy of fosbretabulin disodium combined with radiofrequency ablation in lung cancer
.
Radiat Res
.
2022
;
198
(
5
):
467
74
.
90.
Li
M
,
Hao
B
,
Zhang
M
,
Reiter
RJ
,
Lin
S
,
Zheng
T
, et al
.
Melatonin enhances radiofrequency-induced NK antitumor immunity, causing cancer metabolism reprogramming and inhibition of multiple pulmonary tumor development
.
Signal Transduct Target Ther
.
2021
;
6
(
1
):
330
.
91.
Yin
J
,
Dong
J
,
Gao
W
,
Wang
Y
.
A case report of remarkable response to association of radiofrequency ablation with subsequent Atezolizumab in stage IV nonsmall cell lung cancer
.
Medicine
.
2018
;
97
(
44
):
e13112
.
92.
Ma
S
,
Li
X
,
Wang
X
,
Cheng
L
,
Li
Z
,
Zhang
C
, et al
.
Current progress in CAR-T cell therapy for solid tumors
.
Int J Biol Sci
.
2019
;
15
(
12
):
2548
60
.
93.
Cao
B
,
Liu
M
,
Wang
L
,
Zhu
K
,
Cai
M
,
Chen
X
, et al
.
Remodelling of tumour microenvironment by microwave ablation potentiates immunotherapy of AXL-specific CAR T cells against non-small cell lung cancer
.
Nat Commun
.
2022
;
13
(
1
):
6203
.
94.
Shao
C
,
Yang
M
,
Pan
Y
,
Xie
D
,
Chen
B
,
Ren
S
, et al
.
Case report: abscopal effect of microwave ablation in a patient with advanced squamous NSCLC and resistance to immunotherapy
.
Front Immunol
.
2021
;
12
:
696749
.
95.
Bäcklund
M
,
Freedman
J
.
Microwave ablation and immune activation in the treatment of recurrent colorectal lung metastases: a case report
.
Case Rep Oncol
.
2017
;
10
(
1
):
383
7
.
96.
Yu
W
,
Sun
J
,
Wang
T
,
Du
Y
.
The effect of microwave ablation combined with anti-PD-1 monoclonal antibody on T cell subsets and long-term prognosis in patients suffering from non-small-cell lung cancer
.
Comput Math Methods Med
.
2022
;
2022
:
7095423
.
97.
Wei
Z
,
Yang
X
,
Ye
X
,
Huang
G
,
Li
W
,
Han
X
, et al
.
Camrelizumab combined with microwave ablation improves the objective response rate in advanced non-small cell lung cancer
.
J Cancer Res Ther
.
2019
;
15
(
7
):
1629
34
.
98.
Huang
Y
,
Wang
J
,
Hu
Y
,
Cao
P
,
Wang
G
,
Cai
H
, et al
.
Microwave ablation plus camrelizumab monotherapy or combination therapy in non-small cell lung cancer
.
Front Oncol
.
2022
;
12
:
938827
.
99.
Vollmer
J
,
Krieg
AM
.
Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists
.
Adv Drug Deliv Rev
.
2009
;
61
(
3
):
195
204
.
100.
Machlenkin
A
,
Goldberger
O
,
Tirosh
B
,
Paz
A
,
Volovitz
I
,
Bar-Haim
E
, et al
.
Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity
.
Clin Cancer Res
.
2005
;
11
(
13
):
4955
61
.
101.
Alteber
Z
,
Azulay
M
,
Cafri
G
,
Vadai
E
,
Tzehoval
E
,
Eisenbach
L
.
Cryoimmunotherapy with local co-administration of ex vivo generated dendritic cells and CpG-ODN immune adjuvant, elicits a specific antitumor immunity
.
Cancer Immunol Immunother
.
2014
;
63
(
4
):
369
80
.
102.
Zhang
M
,
Yin
T
,
Lu
Y
,
Feng
H
.
The application of cytidyl guanosyl oligodeoxynucleotide can affect the antitumor immune response induced by a combined protocol of cryoablation and dendritic cells in Lewis lung cancer model
.
Med Sci Monit
.
2016
;
22
:
1309
17
.
103.
Vrabel
MR
,
Schulman
JA
,
Gillam
FB
,
Mantooth
SM
,
Nguyen
KG
,
Zaharoff
DA
.
Focal cryo-immunotherapy with intratumoral IL-12 prevents recurrence of large murine tumors
.
Cancers (Basel)
.
2023
;
15
(
8
):
2210
.
104.
Yu
Z
,
Wang
D
,
Qi
Y
,
Liu
J
,
Zhou
T
,
Rao
W
, et al
.
Autologous-cancer-cryoablation-mediated nanovaccine augments systematic immunotherapy
.
Mater Horiz
.
2023
;
10
(
5
):
1661
77
.
105.
Adam
LC
,
Raja
J
,
Ludwig
JM
,
Adeniran
A
,
Gettinger
SN
,
Kim
HS
.
Cryotherapy for nodal metastasis in NSCLC with acquired resistance to immunotherapy
.
J Immunother Cancer
.
2018
;
6
(
1
):
147
.
106.
Feng
J
,
Guiyu
D
,
Xiongwen
W
.
The clinical efficacy of argon-helium knife cryoablation combined with nivolumab in the treatment of advanced non-small cell lung cancer
.
Cryobiology
.
2021
;
102
:
92
6
.
107.
Meng
L
,
Zhang
Z
,
Zhang
X
,
Zhang
X
,
Wei
Y
,
Wu
B
, et al
.
Case report: local cryoablation combined with pembrolizumab to eliminate lung metastases from ovarian clear cell carcinoma
.
Front Immunol
.
2022
;
13
:
1006500
.
108.
Ma
S
,
Caligiuri
MA
,
Yu
J
.
Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy
.
Trends Immunol
.
2022
;
43
(
10
):
833
47
.
109.
Lin
M
,
Liang
SZ
,
Wang
XH
,
Liang
YQ
,
Zhang
MJ
,
Niu
LZ
, et al
.
Clinical efficacy of percutaneous cryoablation combined with allogenic NK cell immunotherapy for advanced non-small cell lung cancer
.
Immunol Res
.
2017
;
65
(
4
):
880
7
.
110.
Wang
S
,
Wang
X
,
Zhou
X
,
Lyerly
HK
,
Morse
MA
,
Ren
J
.
DC-CIK as a widely applicable cancer immunotherapy
.
Expert Opin Biol Ther
.
2020
;
20
(
6
):
601
7
.
111.
Yuanying
Y
,
Lizhi
N
,
Feng
M
,
Xiaohua
W
,
Jianying
Z
,
Fei
Y
, et al
.
Therapeutic outcomes of combining cryotherapy, chemotherapy and DC-CIK immunotherapy in the treatment of metastatic non-small cell lung cancer
.
Cryobiology
.
2013
;
67
(
2
):
235
40
.
112.
Silvestrini
MT
,
Ingham
ES
,
Mahakian
LM
,
Kheirolomoom
A
,
Liu
Y
,
Fite
BZ
, et al
.
Priming is key to effective incorporation of image-guided thermal ablation into immunotherapy protocols
.
JCI Insight
.
2017
;
2
(
6
):
e90521
.
113.
Shi
L
,
Wang
J
,
Ding
N
,
Zhang
Y
,
Zhu
Y
,
Dong
S
, et al
.
Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy
.
Nat Commun
.
2019
;
10
(
1
):
5421
.
114.
Shen
Y
,
Chen
L
,
Guan
X
,
Han
X
,
Bo
X
,
Li
S
, et al
.
Tailoring chemoimmunostimulant bioscaffolds for inhibiting tumor growth and metastasis after incomplete microwave ablation
.
ACS Nano
.
2021
;
15
(
12
):
20414
29
.
115.
Kroeze
SGC
,
van Melick
HHE
,
Nijkamp
MW
,
Kruse
FK
,
Kruijssen
LWJ
,
van Diest
PJ
, et al
.
Incomplete thermal ablation stimulates proliferation of residual renal carcinoma cells in a translational murine model
.
BJU Int
.
2012
;
110
(
6 Pt B
):
E281
6
.
116.
Li
G
,
Kong
J
,
Dong
S
,
Niu
H
,
Wu
S
,
Sun
W
.
Circular BANP knockdown inhibits the malignant progression of residual hepatocellular carcinoma after insufficient radiofrequency ablation
.
Chin Med J
.
2022
.
117.
Kong
J
,
Yao
C
,
Dong
S
,
Wu
S
,
Xu
Y
,
Li
K
, et al
.
ICAM-1 activates platelets and promotes endothelial permeability through VE-cadherin after insufficient radiofrequency ablation
.
Adv Sci
.
2021
;
8
(
4
):
2002228
.
118.
Pang
JS
,
Wen
DY
,
He
RQ
,
Chen
G
,
Lin
P
,
Li
JH
, et al
.
Incomplete thermal ablation-induced up-regulation of transcription factor nuclear receptor subfamily 2, group F, member 6 (NR2F6) contributes to the rapid progression of residual liver tumor in hepatoblastoma
.
Bioengineered
.
2021
;
12
(
1
):
4289
303
.
119.
Tan
J
,
Tang
T
,
Zhao
W
,
Zhang
ZS
,
Xiao
YD
.
Initial incomplete thermal ablation is associated with a high risk of tumor progression in patients with hepatocellular carcinoma
.
Front Oncol
.
2021
;
11
:
760173
.