Background: Although substantial efforts have been made by researchers to develop drugs, a disappointing reality is that the emergence of drug resistance is an unavoidable reality for the majority of patients. In recent years, emerging evidence suggests a connection between drug resistance and immune dysregulation. Summary: As a ubiquitously distributed, versatile innate immune cell, macrophages play essential roles in maintaining tissue homeostasis in a steady state. Nevertheless, it is becoming aware that macrophages undermine the action of therapeutic drugs across various disease types. Reprogramming macrophage function has been proven to be effective in restoring patient responsiveness to treatment. Herein, we comprehensively reviewed how macrophages respond to drugs and the mechanisms by which they contribute to treatment unresponsiveness in cancer, inflammatory diseases, and metabolic diseases. In addition, future prospects in macrophage-based combination therapy were discussed. Key Messages: Targeting macrophages is a promising strategy for overcoming drug resistance in immune disorders.

Over the past decades, pharmaceutical companies and laboratories have invested substantial funds in the hope of developing new drugs for disease treatment. Disappointingly, a large proportion of patients evolve drug resistance that leads to the final failure of treatment, posing a great obstacle in achieving satisfactory therapeutic outcomes. Drug resistance can be classified into intrinsic resistance (also called primary resistance) and acquired resistance (also called secondary resistance). The former represents a situation in which patients do not respond to an initial treatment, and the latter means that patients show initial clinical improvement but gradually lose the response to drugs later on [1, 2]. Some of these patients may permanently lose the opportunity to recover from the illness. In recent years, a mounting body of evidence has revealed the close association between drug resistance and the dysfunction of host immune system [3‒5]. Among the primary immune compartments, macrophages exhibit a widespread distribution throughout nearly all tissues. With the progression of the disease, the chemoattractive signals from the involved tissues further recruit large amounts of peripheral monocytes which differentiate into macrophages to replenish the local macrophage pool [6]. Therefore, macrophages typically constitute the predominant population of tissue-resident immune cells. Unlike many terminally differentiated cells, macrophages exhibit extreme plasticity. Their phenotype and function consistently change in response to environmental cues. In this review, we will discuss the current understanding of how macrophages limit the therapeutic responses of drugs in disease treatment and provide future directions for overcoming macrophage-mediated drug resistance.

Macrophages are versatile innate immune cells that are present throughout the body. The tissue-resident macrophages can develop from extraembryonic yolk sac or be replenished by peripheral monocytes [7]. Based on their phenotype and functional status, macrophages can be classified into two primary types: M1 and M2. The M1 type, also known as classically activated macrophages, is induced upon stimulation by lipopolysaccharide or interferon-γ (IFN-γ). The M2 type, also known as alternatively activated macrophages, is induced upon stimulation by interleukin-4 (IL-4) or interleukin-13 (IL-13). M1 macrophages have potent pro-inflammatory, phagocytic, and antigen-presenting capacities that are required for the host defense against pathogens, as well as the induction of effective anti-tumor immunity. However, excessive activation of M1 macrophages causes unresolved inflammation and tissue damage. In contrast, M2 macrophages are characterized by their anti-inflammatory, pro-angiogenic, and tissue repair properties, while their immunosuppressive nature usually leads to tumor immune evasion [8].

It should be noted that the M1-M2 system is an oversimplified taxonomy used to depict the two extreme polarization statuses of macrophages. Under in vivo scenarios, tissue-resident macrophages exhibit mixed phenotypes, possessing both M1 and M2 properties [9]. Therefore, we used “M1-like macrophages” or “M2-like macrophages” to depict their functional properties. Besides, macrophages are sensitive to environmental changes and thus can rapidly undergo functional reprogramming upon receiving external signals, such as exposure to drugs. Furthermore, macrophage-mediated intercellular crosstalk has profound influences on the functions of adaptive immune cells, epithelial cells, fibroblasts, endothelial cells, and neurons [10]. In the following sections, we will highlight the way that macrophages respond to therapeutic drugs and the consequent impacts on treatment outcomes.

Macrophages located in the tumor microenvironment (TME) (also known as tumor-associated macrophages [TAMs]) have profound impacts on the initiation, progression, and metastasis of tumors. TME usually drives the reprogramming of TAMs into a pro-tumor phenotype. Therefore, in most cases, high TAM infiltration is correlated with an unfavorable prognosis in cancer patients. Besides acting as a culprit in aiding tumor development, emerging evidence has unveiled TAMs as crucial determinants for the unresponsiveness to anti-tumor therapeutics (Fig. 1).

Fig. 1.

Impacts of macrophages on therapy responses in cancer. The M2-like TAMs are major contributors that cause multidrug resistance by various mechanisms, such as secreting immunosuppressive cytokines (TGF-β, COX2, IL-6) or chemokines (CCL2, IL-8, CCL20), expressing immunosuppressive ligands (PD-L1, CD39), or protecting tumor cells from drug-induced apoptosis.

Fig. 1.

Impacts of macrophages on therapy responses in cancer. The M2-like TAMs are major contributors that cause multidrug resistance by various mechanisms, such as secreting immunosuppressive cytokines (TGF-β, COX2, IL-6) or chemokines (CCL2, IL-8, CCL20), expressing immunosuppressive ligands (PD-L1, CD39), or protecting tumor cells from drug-induced apoptosis.

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Chemotherapy

Macrophages counteract the effectiveness of chemotherapy drugs via multiple mechanisms. In cholangiocarcinoma patients (n = 70), low infiltration of mannose receptor 1 (MRC1/CD206)+ macrophages was associated with improved survival after chemotherapy [11]. In pancreatic adenocarcinoma patients (n = 6), the efficacy of FOLFIRINOX chemotherapy was greatly improved by the simultaneous administration of a C-C motif chemokine receptor 2 (CCR2) inhibitor, which prevented macrophage infiltration into the TME [12]. Through performing single-cell RNA sequencing, Zhang et al. [13] identified that a proliferating resident macrophage subset, featured by the high expression of Ki-67, was associated with chemotherapy resistance in pancreatic ductal adenocarcinoma patients. In addition, macrophage depletion by a colony-stimulating factor-1 receptor (CSF-1R) inhibitor sensitized breast cancer cells to paclitaxel treatment in mice [14].

TAM-derived soluble factors can mediate the pro-tumor intercellular crosstalk that contributes to the chemoresistance of tumors. Li et al. [15] reported that TAM-derived transforming growth factor-beta (TGF-β) upregulated hepatic leukemia factor (HLF) expression in breast cancer cells, which transactivated gamma-glutamyl transferase 1 (GGT1) to induce cisplatin resistance. TAMs were associated with cisplatin resistance in epithelial ovarian cancer patients (n = 62) via exosomal delivery of miR-223 [16]. In colorectal cancer (CRC), interleukin-6 (IL-6) secreted by macrophages activated signal transducer and activator of transcription 3 (STAT3) signaling in tumor cells, leading to the induction of chemoresistance [17]. Cathepsin-expressing macrophages prevented tumor cell death induced by paclitaxel, etoposide, and doxorubicin. The combinatorial treatment of chemotherapy drugs and cathepsin inhibitor had a stronger anti-tumor effect in mice [18]. The other TAM-derived factors that drive tumor chemoresistance include C-C motif chemokine ligand 5 (CCL5) [19], C-C motif chemokine ligand 20 (CCL20) [20], and pyrimidines [21].

A panel of chemotherapy drugs has been reported to induce the M2-like polarization of TAMs, leading to drug resistance. For example, cisplatin- or carboplatin-treated tumor cells had a potent capacity to induce M2-like macrophage differentiation in a prostaglandin E2 (PGE2)/IL-6-dependent manner, indicating that PGE2 or IL-6 inhibition might increase the anti-tumor effects of these two drugs [22]. Silencing lncRNA MRI155 host gene (MIR155HG) expression in TAMs inhibited their M2-like polarization and reduced oxaliplatin resistance in CRC cells [23]. Similar to platinum drugs, paclitaxel and gemcitabine have also been reported to facilitate the functions of M2-like TAMs in vitro and in vivo [24, 25], leading to the compromised drug effect.

It is well-recognized that cancer stem cells are more resistant to chemotherapy than normal cancer cells [26]. In this regard, Jinushi et al. [27] reported that milk fat globule-epidermal growth factor-VIII (MFG-E8) secreted from TAMs activated STAT3 and Sonic Hedgehog signaling in cancer stem cells, limiting their sensitivity to cisplatin in mice. Macrophage-derived interleukin-1β (IL-1β) upregulated intercellular adhesion molecule 1 (ICAM1) expression on tumor cells to promote their stemness, endowing the chemoresistant property of head and neck squamous cell carcinoma [28].

In recent years, growing attention has been paid to a newly characterized form of cell death –ferroptosis. Despite showing encouraging perspectives, tumors can exploit macrophages to protect against ferroptotic death. Cang et al. [29] reported that erastin, a typical ferroptosis inducer, enhanced interleukin-8 (IL-8) production by TAMs in murine ovarian cancer models, resulting in the increased metastatic capacity of ferroptosis-resistant tumor cells. In addition, ferroptosis inducers significantly upregulated programmed death ligand 1 (PD-L1) expression on TAMs, the combination of ferroptosis therapy and anti-PD-L1 antibody exhibited a stronger anti-tumor effect than monotherapy in mice [30], highlighting the rationale behind combining chemotherapy and immunotherapy.

Immunotherapy

As one of the representatives and fastest developing areas in the 21st century, tumor immunotherapy has irreplaceable advantages due to its high specificity, relatively milder adverse effects, and long-lasting effects compared to traditional therapeutics. However, the efficacy of immunotherapy is greatly impaired by the immunosuppressive TME in which TAMs are major culprits. The durable responses of immunotherapy rely on the infiltration of cytotoxic T lymphocytes (CTLs) into the TME [31]. However, the stromal macrophages restricted the motility of cluster of differentiation 8+ (CD8+) CTLs to prevent their migration into tumor nests, thereby rendering anti-programmed death-1 (anti-PD-1) therapy ineffective. Thus, the co-treatment of anti-PD-1 and the CSF-1R inhibitor pexidartinib exhibited pronounced tumor inhibition in mice [32]. Triggering receptor expressed on myeloid cells 2 (TREM2)+ TAMs caused the exhaustion of CD8+ CTLs and led to anti-PD-1 resistance. Anti-TREM2 restored the activation of CTLs and improved the response to PD-1 blockade in murine colon carcinoma [33]. Hypoxia induced a triggering receptor expressed on myeloid cells 1 (TREM1)+ TAM population, which secreted CCL20 to recruit C-C motif chemokine receptor 6 (CCR6)+ regulatory T cells, thereby contributing to anti-PD-L1 therapy resistance in mice [34]. Histone deacetylase (HDAC) inhibitors reprogrammed TAMs into an anti-tumor phenotype, while also upregulating PD-L1 expression on TAMs. The double blockade of HDAC activity and the PD1/PD-L1 axis showed remarkable synergistic anti-tumor effect in murine melanoma, breast cancer, and lung cancer models [35]. Hepatocellular carcinoma patients (n = 8) resistant to anti-PD1 therapy had elevated expression of circTMEM181, which increased ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39) expression in macrophages, leading to immunosuppression in mice [36]. Histamine, an allergy mediator, caused resistance to anti-PD-L1 and anti-cytotoxic lymphocyte antigen-4 (anti-CTLA-4) therapies through inducing V-domain Ig suppressor of T-cell activation (VISTA) expression on mouse macrophages [37].

Although PD-L1 expression is ubiquitously found on tumor cells and various stromal cells, recent clinical evidence has indicated that high PD-L1 expression on TAMs was significantly associated with longer survival in lung cancer patients who received anti-PD-1 treatment. In contrast, PD-L1 expression on tumor cells did not show a significant correlation with patient survival according to three retrospective Yale non-small-cell lung cancer cohorts (n = 489) [38]. In murine colon cancer, ovarian cancer, and melanoma models, PD-L1 expression on host antigen-presenting cells, but not on tumor cells, determined the anti-PD-L1-mediated tumor inhibition. Consistently, in melanoma patients (n = 26) and ovarian cancer patients (n = 17), PD-L1 expression on macrophages and dendritic cells predicted the efficacy of anti-PD1 therapy [39]. Actually, although PD-L1 can inhibit anti-tumor immunity, macrophages with high PD-L1 expression do not necessarily mean they are functionally immunosuppressive. Some potent PD-L1-inducing cytokines are also inducers of M1-like macrophages, as exemplified by tumor necrosis factor-α (TNF-α) and IFN-γ [40, 41], which are highly anti-tumoral. Thus, high PD-L1 expression sometimes represents a strong immunostimulatory status of macrophages, with PD-L1 being induced just to form a negative feedback mechanism.

In addition to the traditional immune checkpoints, the novel “phagocytic checkpoint” in macrophages has been attracting increasing attention in recent years. The two known phagocytic checkpoint proteins are integrin associated-protein (IAP/CD47) and heat stable antigen (HAS/CD24). Their engagement with signal regulatory protein α (SIRPα) and sialic acid-binding immunoglobulin-like lectin-10 (Siglec-10) on macrophages counteracts macrophage-mediated phagocytosis of tumor cells, generating a “do not eat me” signal [42]. Several drugs that target CD47/SIRPα or CD24/Siglec-10 interaction have already entered clinical trials [43, 44]. Although clinical data are still unavailable at present, it is no doubt that macrophage functions are decisive for the effectiveness of phagocytic checkpoint therapies. To date, several preclinical studies have reported that CD47/SIRPα blockade is more effective when combined with other types of therapies (see below).

Radiotherapy

Radiation can significantly alter the TME. Leblond et al. [45] reported that X-ray radiation caused a reduction in the total number of macrophages in glioblastoma. However, compared to M1-like TAMs, the pro-tumor M2-like TAMs were more resistant to X-ray radiation in mice. After radiotherapy, reprogramming M2-like TAMs into M1-like phenotype by SIRPα knockout increased the infiltration of tumoricidal T cells and NK cells. These changes reversed radiation-triggered immunosuppression in patient-derived glioma xenografts [46]. Akkari et al. [47] identified a radiation-specific macrophage subset in glioblastoma that promotes resistance to ionizing radiation. CSF-1R inhibition by BLZ945 improved the response to radiotherapy. In breast cancer cells after radiation or in radioresistant breast cancer cells, the expression of CD47 and human epidermal growth factor receptor 2 (HER2) was markedly increased. The dual inhibition of CD47 and HER2 synergized with radiotherapy to suppress tumor growth by facilitating macrophage-mediated phagocytosis [48]. The synergistic tumoricidal effect of CD47 blockade plus radiotherapy was also observed in murine CRC and melanoma models [49]. Intriguingly, the combined therapy with irradiation and CD47 blockade induced an “abscopal” effect that suppressed the development of distant nonirradiated tumors in mice. This effect depends on the migration of macrophages after the combinatorial therapy [50].

Targeted Therapy

Targeted therapy refers to the precise intervention of specific molecules that drive the malignant behaviors of tumors, mainly including oncogenic and pro-angiogenic proteins. Nevertheless, primary or acquired resistance to targeted therapy drugs is commonly observed in cancer patients. Emerging evidence has linked the failure of targeted therapy with TAMs. For example, IL-8 produced by breast cancer TAMs restricted the effect of lapatinib, an inhibitor of epidermal growth factor receptor (EGFR) and HER2, by activating EGFR signaling [51]. In murine head and neck squamous cell carcinoma, tumor cells mediated the M2-like polarization of TAMs, which in turn secreted C-C motif chemokine ligand 15 (CCL15) to induce gefitinib (an EGFR inhibitor) resistance. Metformin disrupted this tumor-TAM crosstalk to enhance gefitinib sensitivity [52]. Suppressing M2-like TAM polarization by blocking STAT3/IL-4 signaling reduced the resistance of lung cancer cells to osimertinib (an EGFR inhibitor) [53]. In addition, TAMs limited the function of ruxolitinib, a Janus kinase (JAK)/STAT inhibitor, by producing cyclooxygenase-2 (COX-2). The dual inhibition of COX-2 and JAK/STAT showed a more potent tumoricidal effect than ruxolitinib monotherapy in mice [54]. Through performing single-cell RNA sequencing, Tirier et al. [55] identified that a TAM subset, characterized by the expression of CD206, signaling lymphocyte activation molecule family member 5 (SLAMF5/CD84), and CD38, was correlated with multidrug resistance in multiple myeloma patients (n = 20).

For breast cancer and prostate cancer, which rely on sex hormones for their growth, endocrine therapy is a regular approach. The representative drugs are tamoxifen (a selective estrogen receptor modulator) and enzalutamide (an androgen receptor [AR] inhibitor), whose actions were compromised by macrophages. TAM-derived C-C motif chemokine ligand 2 (CCL2) and IL-6 induced tamoxifen resistance of breast cancer cells through activating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling and STAT3 signaling, respectively [56, 57]. In prostate cancer, tumor cells produced high levels of semaphorin 3A (SEMA3A) to induce M2-like polarization of TAMs, leading to enzalutamide resistance [58]. Activin A-producing TAMs boosted fibronectin (FN1)-integrin alpha 5 (ITGA5)-tyrosine kinase Src (SRC) signaling in murine prostate cancer that contributed to enzalutamide resistance [59]. In another report, TAM depletion by anti-colony-stimulating factor-1 (anti-CSF-1) decreased androgen production and AR signaling in murine prostate cancer, making prostate tumors more sensitive to enzalutamide [60].

Antiangiogenic agents are another category of targeted therapy drugs, such as anti-vascular endothelial growth factor (VEGF)-A antibody bevacizumab and B20. Liu et al. [61] reported that TNF-α secreted by M2b macrophages (CD11b+ CD86high IL10high) contributed to bevacizumab resistance in murine triple-negative breast cancer. Reprogramming of M2-like macrophages into M1-like phenotype by a bispecific antibody targeting angiopoietin-2 (Ang-2)/VEGF-A sensitized glioblastoma to B20 therapy in mice [62]. Interestingly, antiangiogenic therapy led to increased CD47 expression on tumor cells, thereby limiting its efficacy by potentiating the “do not eat me” signal in macrophages. Thus, the antiangiogenic therapy could be enhanced through the concurrent administration of CD47 blockade in murine lung carcinoma [63].

Danger Signals and Therapy Resistance

Regardless of the type of treatment, anti-tumor drugs induce cell death which is inevitably accompanied by the massive release of so-called danger-associated molecular patterns (DAMPs). DAMPs are a group of molecules released upon cell damage or under stress [64]. The well-established DAMPs include heat shock proteins (HSPs), high mobility group box 1 (HMGB1), interleukin-33 (IL-33), and adenosine triphosphate. HMGB1 secreted from tumor cells promoted the progression of esophageal squamous cell carcinoma and osteosarcoma by inducing M2-like differentiation of TAMs [65, 66]. Likewise, TAMs exhibited higher pro-tumor or pro-angiogenic capacities when exposed to HSP110 in vivo and HSP27 in vitro [67, 68]. Our group has reported that necrotic tumor cells release IL-33 to facilitate the expansion and immunosuppressive function of myeloid cells in mice [69]. Although extracellular adenosine triphosphate generally boosts anti-tumor immunity, it can be rapidly converted into adenosine by ENTPD1 (CD39) and ecto-5′-nucleotidase (CD73). Adenosine prevented the M1-like polarization of macrophages in vitro [70] and compromised the therapeutic efficacy of anti-CTLA4 antibody in murine melanoma [71]. However, targeting DAMPs remains challenging since multiple DAMPs might act synergistically to induce immunosuppression, it is still unclear whether there is a dominant DAMP in a specific TME.

Summary

From macrophages’ own perspective, they are unable to distinguish between normal and malignant tissues. Rather, they see tumors as a “never-healing wound” after being challenged with anti-tumor drugs [72]. Moreover, the “smart” growing tumors release various signals that resemble those from true wounds. Therefore, macrophages are misdirected to polarize into an M2-like phenotype with tissue repair capacity, characterized by high expression of anti-inflammatory cytokines and pro-angiogenic mediators. Therefore, the key principle for overcoming macrophage-mediated drug resistance in cancer therapy is to “reeducate” TAMs to awaken their immunostimulatory and tissue disruptive potential.

Macrophages are the first-line immune cells that rapidly sense and respond to external pathogens, particularly at host-environment interfaces such as the skin, lung, and digestive tract. Although the proper activation of macrophages is indispensable for the clearance of invading pathogens, their excessive or long-term activation leads to inflammation and subsequent tissue damage. Thus, targeting macrophage function is pivotal for optimizing the therapeutic efficacy of anti-inflammatory drugs (Fig. 2).

Fig. 2.

Impacts of macrophages on therapy responses in inflammation. The M1-like macrophages compromise the effectiveness of anti-inflammatory drugs primarily through secreting pro-inflammatory cytokines or producing MMP12 which cleaves the therapeutic mAbs.

Fig. 2.

Impacts of macrophages on therapy responses in inflammation. The M1-like macrophages compromise the effectiveness of anti-inflammatory drugs primarily through secreting pro-inflammatory cytokines or producing MMP12 which cleaves the therapeutic mAbs.

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Inflammation is closely associated with the hyperactivation of immune responses against exogenous or endogenous antigens, corresponding to infectious diseases or autoimmune diseases, respectively. The common anti-inflammatory drugs include (1) neutralizing antibodies against inflammatory cytokines; (2) inhibitors of inflammatory signaling proteins; (3) antibodies targeting immune cell function; (4) non-biological drugs. However, a significant number of patients failed to benefit from drug treatment.

Antibodies against Inflammatory Cytokines

At present, monoclonal antibodies (mAbs) targeting TNF-α, IL-6, interleukin-12 (IL-12), or interleukin-23 (IL-23) signaling have gained widespread application in clinical practice to treat inflammation, such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA). For the four cytokines, macrophages serve as both major sources and important responder cells. Blocking TNF-α signaling for 8 weeks by etanercept (n = 12) or infliximab (n = 9) led to a remarkable decrease of synovial macrophages in RA patients [73]. In an RA model using human TNF transgenic mice, TNF neutralization by infliximab reduced the number of macrophages in ankles by inhibiting CCL2 expression [74]. Dige et al. [75] reported that anti-TNF-α treatment reduced the levels of soluble hemoglobin-haptoglobin scavenger receptor (sCD163), a macrophage activation marker, in 98 IBD patients. These findings demonstrate that disrupting macrophage function contributes to the therapeutic outcome of TNF-α mAbs. In support of this finding, infliximab-non-responding IBD patients (n = 38) have a higher enrichment of several monocyte/macrophage subsets than infliximab-responding patients (n = 28) [76]. Similar to anti-TNF-α mAb, the IL-6 receptor antibody tocilizumab inhibited the pro-inflammatory activation and infiltration of macrophages in mice [77]. In RA patients, the reduction in macrophage numbers was only observed in responders (n = 37) but not in nonresponders (n = 42) after tocilizumab treatment [78]. For IL-12/IL-23 blockade, reduced macrophage infiltration was observed in psoriatic arthritis patients (n = 8) treated with ustekinumab, an mAb that binds to IL-12 and IL-23 [79]. Although the mechanism by which macrophages influence ustekinumab resistance is still elusive, Pavlidis et al. [80] reported that interleukin-22 (IL-22) led to unresponsiveness to ustekinumab therapy in IBD patients (n = 550) by enhancing neutrophil recruitment. Since macrophages can directly produce IL-22 or control IL-22 production by innate lymphoid cells [81, 82], it is reasonable that macrophage dysfunction is associated with ustekinumab resistance.

Despite their anti-inflammatory function, a considerable proportion of patients develop resistance to anti-TNF-α mAbs, with macrophages being a contributing factor. For example, IBD patients refractory to anti-TNF-α therapy (n = 3) exhibited remarkably high expression of IL-23 in CD14+ intestinal macrophages, the excessive IL-23 production protected lamina propria T cells from apoptosis induced by anti-TNF-α, resulting in resistance to the therapy [83]. Therefore, IL-23 mAbs could be considered to overcome the secondary nonresponse to anti-TNF-α therapy. Apart from IL-23, the macrophage-specific extracellular enzyme matrix metalloproteinase 12 (MMP12) directly mediates the proteolytic cleavage and the consequent inactivation of anti-TNF-α mAbs [84]. Thus, reducing MMP12 production by intestinal macrophages is a feasible approach to decrease drug resistance. Our group also demonstrated that macrophage-derived inflammatory cytokines triggered endoplasmic reticulum stress in the intestinal epithelium, thereby limiting the therapeutic efficacy of TNF-α-neutralizing antibody in colitic mice [85]. Through comparing the cytokine profile of monocytes (the precursors of intestinal macrophages) from infliximab-responding and non-responding IBD patients, Federica et al. [86] found that the levels of IL-1β, TNF-α, interleukin 8 (CXCL8), CCL2, and CCL5 were significantly higher in the non-responding group (n = 8) than those in the responding group (n = 11). Belarif et al. [87] linked T-cell IL-7 receptor (IL-7R) signaling with nonresponsiveness to anti-TNF-α therapy in 500 IBD patients. It is very likely that macrophages are also involved in this process since both IL-7 and IL-7R are highly expressed in macrophages [88]. In support of this hypothesis, macrophages were proven to be the primary effector cells in IL-7-induced arthritis. Importantly, anti-TNF-α therapy significantly reduced the number of IL-17R+ macrophages in the ankles of RA patients (n = 10) [89]. Through conducting a whole-genome meta-analysis, Gaujoux et al. [90] revealed that the increased presence of inflammatory macrophages in infliximab-non-responding IBD patients (n = 8) was associated with the activation of the TREM1/CCR2/C-C motif chemokine ligand 7 (CCL7) axis.

Interestingly, macrophages can be “educated” by TNF-α mAb to skew toward an anti-inflammatory phenotype, which is required for their therapeutic response. For example, Koelink et al. [91] reported that anti-TNF-α mAb treatment increased interleukin-10 (IL-10) production by macrophages in mice, which conferred protection against intestinal inflammation. In IBD patients, the IL-10/IFN-γ expression ratio was elevated in individuals who responded to infliximab and adalimumab but not in nonresponders after treatment (n = 7/group), indicating that enhancing IL-10 production by macrophages could potentially overcome resistance to anti-TNF-α therapy.

Inhibitors Targeting Inflammatory Pathways

In many cases, neutralizing a single pro-inflammatory cytokine has limited effectiveness. Therefore, inhibitors that target signal transduction pathways shared by multiple pro-inflammatory mediators have come to researchers’ attention in recent years [92]. A representative example is inhibitors for JAK/STAT signaling, which is used by interferons, interleukin-2 (IL-2), IL-6, IL-12, IL-23, etc. Several JAK inhibitors have gained Food and Drug Administration (FDA) approval including tofacitinib, baricitinib, upadacitinib, abrocitinib, and ruxolitinib [93]. The indications of JAK inhibitors include IBD, RA, ankylosing spondylitis, atopic dermatitis, psoriasis, alopecia areata, etc. [94].

Despite the fact that JAK/STAT pathways are downstream of a range of pathogenic mediators, unfortunately, they are also utilized by certain anti-inflammatory cytokines. For instance, we and others have shown that IL-10/JAK1/STAT3 signaling in macrophages is essential for preventing the progression of various inflammatory disorders [95, 96]. Indeed, tofacitinib treatment impaired IL-10/interleukin-10 receptor (IL-10R) signaling in human macrophages [97]. Additionally, IL-4 and IL-13 signal through JAK2/STAT6 signaling to drive the polarization of M2-like macrophages [98]. Therefore, the disrupted anti-inflammatory signaling in macrophages by JAK inhibitors might contribute to treatment failure or at the very least, compromise their therapeutic effectiveness.

Antibodies Targeting Immune Cell Function

The principle of this type of drug is to block the recruitment or induce the apoptosis of pathogenic immune cells. The former can be exemplified by vedolizumab, an antibody against α4β7 integrin which prevents T-cell infiltration into the inflamed tissues [99]. Surprisingly, Zeissig et al. [100] reported that vedolizumab treatment did not obviously change the abundance and phenotype of intestinal T cells. Instead, vedolizumab prominently reduced or elevated the abundance of M1-like macrophages or M2-like macrophages, respectively. This shifted M1/M2 signature was only observed in IBD patients who achieved clinical remission upon vedolizumab administration (n = 9) but not in those who did not respond to treatment (n = 3) [100]. Additionally, Liu reported that M1-like macrophages were preferentially enriched in the mucosa of vedolizumab-response IBD patients (n = 29) compared to nonresponders (n = 31) [76]. This evidence clearly demonstrates that macrophages can contribute to the failure of vedolizumab treatment. The specific macrophage subpopulations and key effector molecules still await further elucidation.

In autoimmune diseases, the depletion of B cells with anti-CD20 mAbs (e.g., rituximab) prevents the production of autoantibodies. In addition to reducing B-cell numbers, rituximab treatment also decreased the abundance of synovial macrophages in RA patients (n = 82). However, the reduction in macrophage appeared not correlated with the therapeutic response [78].

Conventional Non-Biological Drugs

The representative conventional, anti-inflammatory drugs include methotrexate, corticosteroids, azathioprine, and 5-aminosalicylic acid. These drugs were all reported to dampen the pro-inflammatory activation of macrophages [101‒104]. When used in combination with biological drugs, they can yield a higher benefit. Baranauskaite et al. [105] reported that infliximab plus methotrexate treatment showed higher response rates than methotrexate monotherapy in an open-label study of 115 psoriatic arthritis patients. In a randomized, double-blind trial, the combination therapy with azathioprine and infliximab (n = 107) was found to be superior to azathioprine alone (n = 170) in IBD patients [106]. Of note, although 6-thioguanine (the active metabolite of azathioprine) suppressed the inflammatory activation of macrophages, it also decreased the production of IL-10, a dominant anti-inflammatory mediator in IBD [104]. As mentioned above, anti-TNF-α mAb is a potent inducer of IL-10 in macrophages [91]. This might explain the synergistic effect between azathioprine and infliximab.

Summary

In contrast to the context of cancer, the primary challenge in improving drug response in inflammation is to counteract the functions of M1-like macrophages. In some patients, although drug treatment achieves an initial response, they eventually develop secondary resistance. On the other hand, conventional anti-inflammatory drugs have drawbacks such as relatively high cost, potential side effects, or inconvenience of administration. Therefore, the use of multiple drugs may be unacceptable for some patients. Encouragingly, emerging researchers have discovered the anti-inflammatory properties of many dietary nutrients. For example, we and others reported that mannose suppressed macrophage-mediated inflammation in colitis, endotoxemia, experimental autoimmune encephalomyelitis, and lung inflammation [85, 107‒110]. Thus, the anti-inflammatory natural products might serve as potential candidates used in combination with conventional drugs to enhance their effectiveness. Indeed, mannose was reported to potentiate the anti-colitic effect of mesalazine, a 5-aminosalicylic acid drug [111]. In addition, owing to their proven safety, affordability, and good bioavailability, improved patient compliance can be expected.

Metabolic disease is a type of disorder caused by the defective absorption or metabolism of macronutrients in the body. It has a multifactorial etiology with both genetic and environmental factors involved. Nowadays, it is becoming increasingly evident that metabolic diseases are usually accompanied by the dysfunction of immune responses, featured by low-grade, chronic inflammation [112]. Macrophages express a panel of receptors for hormones and macronutrients, enabling them to respond to drugs in metabolic disorders (Fig. 3).

Fig. 3.

Impacts of macrophages on insulin resistance in metabolic diseases. Macrophages-induced low-grade, chronic inflammation promotes insulin resistance, which is the primary cause of various metabolic disorders.

Fig. 3.

Impacts of macrophages on insulin resistance in metabolic diseases. Macrophages-induced low-grade, chronic inflammation promotes insulin resistance, which is the primary cause of various metabolic disorders.

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Macrophages in Insulin Resistance

Insulin resistance refers to a condition in which cells have impaired sensitivity to exogenous or endogenous insulin and are thus defective in glucose uptake from the blood. Insulin resistance is associated with a cluster of metabolic disorders, including diabetes, obesity, nonalcoholic fatty liver disease (NAFLD), atherosclerosis, and polycystic ovary syndrome [113]. Macrophage-produced inflammatory factors can disrupt the homeostasis of adipose tissues and the functions of adipocytes, leading to impaired insulin sensitivity [114, 115]. Macrophage proliferation in adipose tissue and liver contributes to insulin resistance. Compared to wild-type mice, macrophage-specific proliferation inhibition mouse model (mac-p27 Tg) mice, which have impaired macrophage proliferation, showed significantly lower plasma glucose levels under a high-fat diet (HFD) condition [116]. In macrophage-specific autophagy related 7 (ATG7) knockout mice, the defective autophagy in macrophages skewed them toward an M1-like phenotype and caused insulin resistance in obesity [117]. Targeting macrophage JNK signaling conferred protection against murine obesity-induced insulin resistance [118]. HFD promoted the expression of EGFR and amphiregulin in adipose tissue macrophages. Macrophage-conditional deficiency of EGFR resulted in impaired monocyte recruitment and macrophage accumulation in adipose tissue, thereby ameliorating HFD-induced insulin resistance in mice [119]. Clinical evidence demonstrated that high numbers of CD68+ macrophages were significantly correlated with high fasting insulin levels and insulin resistance [120, 121]. Hypoxia-inducible factor-2α (HIF-2α) signaling in macrophages suppressed NOD-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome, thereby reducing insulin resistance in mice [122]. Murine Kupffer cells (liver resident macrophages) exacerbated obesity-induced hepatic inflammation and insulin resistance by facilitating the recruitment of monocytes in a CCL2-dependent manner [123]. On the other hand, preventing the pro-inflammatory activation of Kupffer cells by nuclear factor-kappa B (NF-κB) inhibition enhanced insulin sensitivity and glucose tolerance in obese mice [124].

In 40 nondiabetic NAFLD patients, the activation of hepatic macrophages was associated with insulin resistance and disrupted glucose metabolism [125]. Promoting the M2-like polarization of Kupffer cells reduced the viability of M1-polarized Kupffer cells in an IL-10-dependent manner, thereby mitigating NAFLD progression in mice [126]. Similarly, dietary monounsaturated fatty acids improved liver insulin sensitivity by enhancing the function of M2-like Kupffer cells [127]. Likewise, M1-like macrophages also contribute to insulin resistance in the development of atherosclerosis in mice and polycystic ovary syndrome in women [128, 129]. Thus, macrophage-mediated inflammation acts as a common factor in the pathogenesis of various metabolic diseases.

So far, numerous pieces of evidence have linked high numbers of macrophages with therapy resistance. However, unlike in animal models, long-term, systemic depletion of macrophages in patients is almost impractical. How to deliver drugs to local macrophages in the disease microenvironment is helpful for achieving desired outcomes, meanwhile minimizing adverse effects. Moreover, the key molecules that drive the anti-tumor function of macrophages might be oncogenic in tumor cells, as exemplified by NF-κB [130]. In this case, the macrophage-specific uptake of drugs is necessary. Another challenge of macrophage-based therapeutics lies in the fact that in some circumstances, macrophages can be replenished from peripheral monocytes, highlighting the need for sustained drug action at disease sites. Macrophages are professional phagocytes with a potent capacity to uptake particles at nano- to macroscale. Thus, the development of nanomaterial technologies has the potential to achieve local macrophage-directed drug delivery, while also increasing drug retention at disease sites to achieve a sustained effect. In addition, antigen-representing cells including macrophages, expressed high levels of several membrane lectins, such as mannose receptors. Owning to this, mannose modification allows for the specific delivery of drugs to macrophages [131, 132].

On the other hand, macrophages exhibit extreme heterogeneity in tissue microenvironments, and their phenotypes consistently change over time. The growing application of single-cell technologies enables us to identify distinct macrophage subsets involved in drug responses. In addition, advancements in multi-omics research can provide powerful tools to dissect the crosstalk among drugs, genes, cells, and endogenous metabolites. A further level of complexity lies in that clinical patients also exhibit substantial individual genetic variance. Even if they show similar resistance to the same drug, the underlying mediators or mechanisms could be completely different. Ideally, we anticipate that drug response can be predicted for each patient prior to treatment. Although challenging, understanding the individual’s drug response is essential for precise and personalized medication.

The effectiveness of targeting stromal components has been confirmed in various types of diseases, especially when monotherapy fails to achieve a satisfactory response. As highly infiltrated stromal cells found in almost all tissues, macrophage responses are sometimes decisive for the therapeutic outcome of drugs. The identification of macrophage-based, targetable molecules will undoubtedly provide significant assistance in overcoming drug resistance to give a dual strike against diseases, yet it still has a long way to go.

Figures were created with BioRender.com.

The authors have no conflicts of interest to declare.

This work is supported by the National Natural Science Foundation of China (82171730 to Peng Xiao).

Peng Xiao and Qian Cao designed the idea. Yimin Ding, Junjie Xu, Wenjuan Yang, Peng Xiao, and Qian Cao wrote the draft of the manuscript. Yimin Ding and Junjie Xu drew the figures. Yimin Ding and Peng Xiao revised the manuscript. Yimin Ding, Junjie Xu, Wenjuan Yang, Peng Xiao, and Qian Cao agreed to be accountable for all aspects of the work.

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