Background: Hepatocellular carcinoma (HCC) remains a significant global health burden with a high mortality rate. Over the past 40 years, significant progress has been achieved in the prevention and management of HCC. Summary: Hepatitis B vaccination programs, the development of direct acting antiviral drugs for Hepatitis C, and effective surveillance strategies provide a profound basis for the prevention of HCC. Advanced surgery and liver transplantation along with local ablation techniques potentially offer cure for the disease. Also, just recently, the introduction of immunotherapy opened a new chapter in systemic treatment. Finally, the introduction of the BCLC classification system for HCC, clearly defining patient groups and assigning reasonable treatment options, has standardized treatment and become the basis of almost all clinical trials for HCC. With this review, we provide a comprehensive overview of the evolving landscape of HCC management and also touch on current challenges. Key Message: A comprehensive and multidisciplinary approach is crucial for effective HCC management. Continued research and clinical trials are imperative to further enhance treatment options and will ultimately reduce the global burden of this devastating disease.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and stands as a formidable global health challenge, ranking as the eighth most common cancer accounting for approximately 830,200 deaths worldwide [1]. Despite advancements in medical research and healthcare, the prognosis for HCC remains grim, necessitating a continuous quest for innovative and effective management strategies [2]. In recent years, a surge of research and clinical investigations has brought forth promising trends and advancements in the field of HCC management. This review article aims to provide a comprehensive analysis of the current state-of-the-art trends and groundbreaking developments in the management of HCC.

The intricate interplay between etiological factors, such as chronic viral hepatitis infections, alcoholic liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), and genetic drivers of hepatocarcinogenesis, renders HCC management a complex endeavor. Understanding the underlying mechanisms driving liver cancer development and exploring novel therapeutic targets has become a main focus in current research efforts, particularly as this is key to precision medicine strategies and personalized therapies to combat HCC with tailored interventions. Concurrently, implementation of regular surveillance of patients at risk, suffering from liver cirrhosis, high-grade fibrosis, and/or chronic hepatitis B, and innovations in diagnostic modalities and surveillance techniques have facilitated early detection and timely intervention, further optimizing treatment outcomes [3].

Cutting-edge surgical techniques such as split liver resection, minimal invasive approaches, and advanced perioperative care have improved the extension of curative resections [4]. Combining those advanced strategies with local ablation may also offer additional patient hope for cure or long-term remission [5]. Finally, liver transplantation has developed into a standard procedure for the treatment of early HCC particularly as well-defined criteria for patient’s section lead to a 5-year survival rate of these patients close to those suffering from other liver disease [6, 7]. However, the scarcity of deceased donor organs for transplantation remains a persistent challenge in some countries [8]. Lastly, regional treatments, such as radiofrequency ablation (RFA) and radioembolization, have emerged as valuable alternatives or adjuncts to surgery, offering minimally invasive approaches to target tumor nodules while preserving liver function [9].

While transarterial chemotherapy and embolization were successfully introduced as TACE [10, 11], systemic therapy remained difficult for a long time. However, with the new era of targeted therapies and immunotherapies, HCC management is currently witnessing a discussion on paradigm shifts toward an increasing and earlier use of systemic treatment modalities. After decades of frustrating clinical trials, Sorafenib, the first FDA-approved systemic therapy for advanced HCC, has paved the way for several multikinase inhibitors now available for the first- and second-line treatment [12]. The availability of immunotherapy-based anticancer treatment, recently demonstrated to also have substantial benefits in HCC, has certainly brought systemic therapy to a new level and is now standard of therapy for most patients [13, 14]. Nonetheless, challenges such as drug resistance and patient heterogeneity in drug response continue to require further investigation [15, 16].

In this review, we aim to provide an in-depth exploration of these current trends and advancements in the management of HCC, offering insights into the challenges, breakthroughs, and future directions that collectively shape the landscape of HCC treatment. By comprehensively analyzing the latest research findings and clinical outcomes, we seek to contribute to the ongoing dialogue surrounding HCC management and inspire further advancements in this critical field of oncology.

HCC is a complex and multifactorial disease with a diverse etiology. Chronic viral hepatitis infections, specifically hepatitis B virus (HBV) and hepatitis C virus (HCV), constitute the most significant risk factors for HCC development. Persistent viral infection leads to chronic inflammation and ongoing liver cell damage, promoting the accumulation of genetic mutations and aberrant cell growth. Other contributing factors include alcohol abuse, which can cause alcoholic liver disease and subsequent cirrhosis, increasing the risk of HCC. MASLD has also emerged as a risk factor, driven by the rising global obesity epidemic. Additionally, exposure to aflatoxin B1, a potent hepatocarcinogen produced by certain Aspergillus species, poses a major risk, particularly in regions with high dietary aflatoxin exposure. Genetic predisposition, iron overload in hereditary hemochromatosis, and alpha-1 antitrypsin deficiency are among other genetic and metabolic factors associated with increased HCC susceptibility [17].

The pathogenesis of HCC involves a complex interplay of various disease mechanisms that contribute to its initiation, promotion, and progression. Chronic inflammation plays a central role, fueling a microenvironment that favors tumor growth and evasion of immune surveillance [18]. Viral infection, especially HBV and HCV, contributes to chronic inflammation through viral replication, immune cell activation, and production of proinflammatory cytokines. Inflammatory signals trigger an intricate network of intracellular pathways, including the PI3K/AKT and NF-κB pathways, leading to enhanced cell survival, proliferation, and evasion of apoptosis. Genetic and epigenetic alterations further drive hepatocellular transformation, affecting key regulators of cell cycle progression, such as TP53 and RB1 [19]. Dysregulation of the Wnt/β-catenin signaling pathway, often observed in HCC, results in abnormal cell proliferation and stem cell-like characteristics [20]. Epigenetic changes, including DNA methylation and histone modifications, also contribute to HCC development by silencing tumor suppressor genes and activating oncogenes [19]. Moreover, alterations in microRNA expression disrupt posttranscriptional regulation, impacting various cellular processes [21].

The diagnosis of HCC requires a comprehensive approach, considering the patient’s clinical history, risk factors, and imaging studies. Given a well-defined population at risk (all patients with liver cirrhosis), surveillance is a critical aspect of managing patients at high risk of developing HCC. High-risk individuals, such as patients with chronic viral hepatitis (HBV or HCV), cirrhosis, or advanced fibrosis, should undergo regular surveillance to detect HCC at an early stage when curative treatment options are still available. Surveillance in advanced fibrosis and MASH patients may be of particular interest as HCC incidence was reported to be particularly increased in MASH. Most recently, the European Association for the Study of the Liver (EASL) clinical practice guideline suggests monitoring and also acknowledges uncertainty regarding the necessity of surveillance for MASLD patients without cirrhosis [22]. The primary surveillance tool remains abdominal ultrasound, as it offers a noninvasive, widely available, and cost-effective method for the detection of focal liver lesions [23]. However, its sensitivity can be influenced by operator experience and patient-related factors, e.g., obesity [24, 25]. The combination of ultrasound with AFP enhances sensitivity but may be limited by its specificity [26]. Therefore, continued research aims to identify additional serum biomarkers with higher sensitivity and specificity to complement imaging surveillance. In any case, regular 6-month surveillance intervals allow for timely initiation of curative or locoregional therapies, potentially improving HCC patient outcomes and overall survival rates [3]. A shorter surveillance interval of 3 months was not proven superior to 6 months [27].

Additionally, contrast-enhanced imaging being it ultrasound (CEUS), CT or MRI has emerged as a valuable tool for real-time imaging [28]. With these modalities, arterial enhancement and delayed portal washout have been characterized as hallmarks of HCC. They are attributed to a predominant arterial perfusion of the tumor as compared to a mostly portal vein-dependent blood supply of the surrounding liver tissue. Guidelines from both the EASL and the European Society for Medical Oncology recommend identifying HCC if a lesion larger than 1 cm in a cirrhotic patient exhibits typical HCC features on dynamic cross-sectional imaging. These criteria demonstrate a low sensitivity but high specificity of 72% and 90% for lesions larger than 2 cm, and 70% and 80% for lesions between 1 and 2 cm, respectively [29]. Additionally, the American Association for the Study of Liver Diseases (AASLD) has adopted the Liver Imaging Reporting and Data System (LI-RADS®) criteria, which integrate supplementary features to evaluate the probability of a lesion being HCC [30]. In MRI, sensitivity of these characteristics was as high as 89% and 96% [31]. As a consequence, tumor biopsy is not mandatory for HCC diagnosis in liver cirrhosis according to current guidelines [22, 30, 32]. A recommendation not shared by all experts and some guidelines currently return to encourage a higher biopsy rate – also in light of recent developments in personalized cancer therapies [32, 33].

The introduction of the LI-RADS provided that a comprehensive system for standardizing the terminology, interpretation, and reporting was a milestone in standardizing observations in individuals at high risk for HCC. Subsequently, it has also been applied to contrast-enhanced ultrasound for HCC diagnosis, CEUS LI-RADS. Besides its quality assuring aspects, it certainly also reduced variability and errors in imaging interpretation but also fostered communication among all health care professionals involved [34‒36].

For decades, the use of biomarkers remained controversial particularly due to their limited sensitivity and specificity. In fact, common HCC guidelines do not recommend the use of AFP, the most prominent biomarker, or any other serum marker for surveillance in patients at risk for HCC [22, 30, 32]. For AFP, sensitivity is only close to 60% with a specificity of up to 90% [37, 38]. However, AFP levels remain normal in 15–30% of patients with advanced stage disease. More recently, the GALAD score, based on gender, age, AFP, AFP-L3, and DCP, was promoted by several groups for early HCC detection [39]. However, also for this integrated score reported sensitivity and specificity showed a wide range in diverse publications from different countries. A more recent prospective cohort study with 397 patients on the GALAD score reported a sensitivity of 55% and a sensitivity of 67% in case of repeated testing [40]. Also, the rate of false-positive findings was up to 23% [41]. Finally, multiple gene expression signatures were published to predict HCC outcome but generally failed to be independently validated. As a result, up to now none of those signatures has made it into clinical routine decision making [42]. Furthermore, recent data on a high rate of positive signatures among randomly selected gene signatures [43] and many signatures being of potential use in other cancers as well [44] raised concerns about the specificity of these signatures and the general approach itself [42].

The Barcelona Clinic Liver Cancer Classification

The Barcelona Clinic Liver Cancer (BCLC) staging differentiates patients into five stages depending on tumor size, number, and location. Since patients suffering from HCC often suffer from underlying liver cirrhosis potentially having a major impact on patients’ fitness, performance status and liver function were included in the BCLC system [45]. Patients with good performance status, preserved liver function, and small and few tumors (single tumor, or ≤3 nodules ≤3 mcm each, stage 0 or A) may be subject to liver transplantation (if single nodule ≤5 cm), resection, or local ablation. These patients have an excellent prognosis of >5 years expected survival. In contrast, patients with extrahepatic spread or diffuse, infiltrative, or extensive bilobular spread of the cancer are subject to systemic treatment. Survival of these patients is limited (>2 years, stage C). Patients with intermediate tumor spread (stage B) are mostly treated by TACE [46]. However, the advent of immunotherapies for HCC created a debate whether at least some of these patients should be offered systemic treatment. This issue is currently investigated in clinical trials such as the ABC-HCC trial [47]. Patients with poor liver function or performance status (stage D) are offered best supportive care.

Overall, a significant correlation between the varying stages of the BCLC staging system and survival rates was repeatedly demonstrated. A recent nationwide study from Korea reported a considerably extended median survival of 81.1 months for patients categorized as BCLC A. Conversely, individuals diagnosed with the most advanced stage, BCLC D, demonstrated a notably shorter median survival of merely 2.2 months [48]. The definition of those clinical stages by the BCLC system has certainly been a major aid in the clinical trial design for patients with HCC and certainly was the basis for significant progress in HCC treatment over the past 3 decades.

Surgery

Surgical approaches, including liver resection and liver transplantation, remain the primary curative treatments for early-stage HCC [22, 30, 32]. Although surgical techniques and perioperative care have certainly improved over the past decades and sophisticate surgery approached such as split liver techniques were introduced [4], surgery in patients with liver cirrhosis remains challenging. It is associated with a significantly increased mortality. Retrospective analyses from the Veterans Affairs (VA) Surgical Quality Improvement Program reported a six times higher postoperative mortality in patients with liver cirrhosis compared to patients with elective surgery [49]. Besides, surgical therapies’ effectiveness can be hindered by several factors. Assessing tumor size and number is crucial as resection is recommended within Milan criteria guidelines. Locally ablative therapies like RFA or MWA should be evaluated as an alternative for tumors under 3 cm and centrally located, as they may be associated with fewer postinterventional liver function issues [50]. Furthermore, infiltration of large vessels negatively impacts prognosis postresection. Also, pronounced portal hypertension adversely affects postoperative survival [51]. However, minimal invasive technics, like robotic-assisted or laparoscopic surgery, may improve postoperative outcome in this special patient group [52]. Reducing trauma of the abdominal wall, liver compression, ascites production, impaired wound healing, and length of hospital stay all contribute to a more favorable outcome [53]. This is even more evident in patients with Child-Pugh B cirrhosis, where postoperative mortality and morbidity could be significantly reduced [54]. Laparoscopic anatomical resections improved the 1- and 3-year disease-free survival by nearly 20% [55]. Thus, minimal invasive liver surgery should be recommended whenever possible in HCC patients particularly in specialized liver centers.

However, surgery (but also local ablation) of HCCs in cirrhotic livers has a high recurrence or de novo rate of 60–70% [56]. With emerging local ablative strategies, surgery was also compared to local ablation. The recent SURF phase III clinical trial (not fully recruited) comparing surgical resection and RFA for HCC ≤3 cm and ≤3 nodules demonstrated comparable 5-year recurrence-free survival rates of 54.7% and 50.5% in the surgery and RFA groups, respectively [57]. However, for multiple tumor nodules, surgery must be assumed to be superior as for each nodule local ablation has a (small) risk of not fully ablating the tumor, rapidly accumulating for multiple tumors [58].

Given the high recurrence rate and increased mortality in patients with liver cirrhosis, liver transplantation provides an excellent opportunity for cure in selected patients with early-stage HCC and underlying cirrhosis [22, 30, 32]. The Milan criteria, established in 1996, define the eligibility for liver transplantation in HCC patients, based on tumor size and number. Mazzaferro and colleagues demonstrated an acceptable recurrence rate and mortality rates comparable to other liver diseases if tumors were smaller than 5 cm or in case of multiple tumors limited to 3 and smaller than 3 cm each [6]. Efforts to expand the donor pool and adopt extended criteria have been explored to increase transplant availability for HCC, e.g., by introducing the UCSF or Up to Seven criteria [59]. However, as nicely demonstrated by the “metro-ticket” concept by Mazzaferro and colleagues, more liberal criteria both in terms of number and size of nodules were associated with an increased recurrence rate [60]. Thus, particularly in many countries with limited organ availability, Milan criteria remain standard in-patient selection [32]. More recently, downstaging approaches were investigated for larger tumors before transplantation. However, carefully selected patients outside Milan criteria can achieve comparable 5-year survival rates. Selection among outside Milan or even BCLC B patients relies on response to neoadjuvant therapy, with successful downstaging resulting in favorable outcomes, notably in “up-to-seven” or UCSF criteria cohorts, with 65–70% 5-year survival rates [59, 61]. A phase III randomized study just recently demonstrated effective and sustained downstaging of eligible HCCs beyond the Milan criteria and improvement of tumor event-free survival and overall survival after transplantation compared with nontransplantation therapies. Given the early closing of the trial, further investigations are definitely needed to apply these concepts in clinical standard treatment [62].

Since liver transplantation offers the advantage of removing both the tumor and the underlying cirrhotic liver, a remaining risk for de novo HCC development, it is thought to minimize the risk of local recurrence and new tumor formation. However, the overall benefit of LTX versus liver resection is not as clear. A recent large meta-analysis demonstrated that the risk of recurrence after resection is threefold compared to that after LTX; mortality after resection for HCC was nearly 50% higher as compared to LTX. Nevertheless, survival between resected and transplanted patients was similar in uninodular disease [63].

Careful evaluation of microvascular invasion may be one of the keys to improved surgery outcome as it was demonstrated to be and independent prognostic indicator of HCC patients after surgery [64, 65]. Furthermore, approximately 80% of patients underwent living donor transplantation and the debate whether survival and recurrence may be higher compared to cadaveric donation mostly used in Western trials is still ongoing [66, 67].

Given the high recurrence rate after resection and limited availability of organs for LTX in many countries, adjuvant treatment has extensively been studied. Soon after Sorafenib became available the STORM trail failed to show a beneficial effect of adjuvant treatment [68]. It was not until recently that the prospective phase III IMbrave 050 trial provided a new momentum to the field as it demonstrated an increased recurrence-free survival for postoperative treatment with Atezolizumab/Bevacizumab in patients with HCC after curative surgery [69]. However, only high-risk patients (tumor size >5 cm, tumor number >3, vascular invasion-microvascular invasion, or macrovascular invasion of the portal vein- and poor tumor differentiation [70]) were selected to be included in this study and data on overall survival are still awaited.

Similar attempts switching immune suppression to Everolimus, an mTOR inhibitor, demonstrated to exhibit antiproliferative properties, after LTX in patients with HCC failed to demonstrate a benefit and reduced recurrence rate in these patients [71].

Local Ablation

Locoregional therapies offer valuable alternative treatment strategies to surgical resection. RFA and microwave ablation (MWA) are commonly employed techniques, using thermal energy to destroy tumor tissue while preserving surrounding healthy liver parenchyma. These minimally invasive approaches are well suited for patients with small, unresectable tumors, up to 3 cm [22, 30, 32]. In patients with nodules larger than 3 cm up to 5 cm, current guidelines recommend a combination of TACE with RFA [50].

Most data are available for RFA, which has been shown to result in similar outcome in selected patients with small single tumor nodules. A large-scale analysis of 18,296 cases from the United States National Cancer Database revealed a comparable overall survival rate in patients with severe liver fibrosis/cirrhosis with a 5-year overall survival 37.3% versus 39.4%. However, when considering the entire cohort of patients, surgical resection was superior with a 5-year overall survival of 29.9% versus 45.7% [72]. Also, the most recent SURF trial did not show any significant differences between surgery and RFA [73].

Furthermore, MWA was also successfully introduced in HCC treatment [9, 74]. But, median duration until progression showed no significant difference between both techniques [75, 76]. Vietti Violi et al. [75] reported a comparable PFS of 16 months after RFA and 12 months after MWA (p value of 0.28). A lack of significant prospective evidence still hinders its broad use in HCC treatment. Finally, external beam radiation may be applied to HCC nodules for focal treatment. Just as for MWA, retrospective data suggest noninferiority to RFA but larger prospective trials are missing [77].

Transarterial Chemoembolization

Transarterial chemoembolization (TACE) involves the injection of chemotherapeutic agents directly into the branch of the hepatic artery supplying the tumor, followed by embolization to induce ischemic tumor necrosis. Two randomized trials confirmed their efficacy in HCC treatment in reducing tumor size, delaying tumor progression, and improving overall survival rates [10, 11]. Since it is considered treatment of choice for patients with intermediate-stage HCC, a well-preserved liver function is essential [22, 30, 46]. Also, it is important to emphasize the necessity for selective vascular access. Ensuring the absence of portal vein thrombosis or complete hepatofugal portal vein perfusion is crucial and macroscopic tumor invasion of specific hepatic vessels can impede TACE [50]. Combining TACE with other treatment modalities, particularly systemic targeted therapies, was repeatedly discussed. Those efforts particularly rely on the observation that if TACE is not totally effective, it may induce a significant neoangiogenetic reaction, as suggested by an increase in VEGF and b-FGF [78]. Thus, tyrosine kinase inhibitors acting on VEGF were hoped to counteract such an increase, impacting survival. However, soon after Sorafenib became available, the SPACE, TACE 2, post-TACE, BRISK-TA [79], and TACTICS trials failed to prove as survival benefit of sorafenib combined with TACE [80‒83] although TACTICS trials [83, 84] improved PFS. In addition, other drugs such as Brivanib and Orantinib also failed to improve survival in patients treated with TACE [79, 85]. Just recently, the EMERALD-1 trial demonstrated for the first time an improved progression-free survival with a combination of TACE, Durvalumab, and Bevacizumab. However, overall survival data must still be awaited [86].

Recently, the drug-eluting beats have been proposed as an alternative to conventional TACE. Although the PRECISION V trial did not show a significant benefit in terms of survival [87], reduced systemic drug exposure and drug-related adverse event still make them part of the current therapeutic arsenal [22, 30, 32].

Finally, it is important to discuss that TACE was initially investigated against standard treatment for HCC which in today’s view would not be adequate. Although TACE certainly has an important role in intermediate-stage HCC treatment, its efficacy needs to be reevaluated now that we have much more efficient drugs at hand. A phase II TACTICS-L trial [88], which combines Lenvatinib and TACE, achieved a very high CR rate of 66.1% and ORR of 85.5% per mRECIST [88]. Thus, results of randomized trials evaluating TACE versus up-to-date immune therapy or TACE plus combination immunotherapy [89] are eagerly awaited [47]. Recently, positive results of EMERALD-1 trial, which combines TACE and Durvalumab plus Bevacizumab, were presented in the ASCO-GI 2024 congress [90].

Systemic Therapy

In recent years, the advent of systemic targeted therapies has revolutionized the treatment landscape for advanced HCC. Sorafenib, a multikinase inhibitor targeting VEGFR, PDGFR, and RAF kinase, was the first targeted therapy approved for advanced HCC. It has shown significant survival benefits, leading to its inclusion as the standard first-line treatment for patients with unresectable or metastatic HCC [12, 91]. Subsequently, several promising targets such as Tivantinib (METIV-HCC trial) [92], Brivanib (BRISK-PS) [93], and others failed to show efficacy after sorafenib treatment in randomized phase III trials and it was not until 2018 that Lenvatinib was approved, demonstrating at least noninferiority to sorafenib (REFLECT trial) [94]. In addition, several second-line treatments were approved after sorafenib treatment: Regorafenib (RESORCE trial) [95], Cabozantinib (CELESTIAL trial) [96], or Ramucirumab for patients with AFP ≥400 U/L (REACH-2 trial) [97]. However, these second-line treatment options remain not available to most patients. Approved for treatment in patients with an underlying liver cirrhosis Child A only. Only 10.1% (Cabozantinib), 7.5% (Regorafenib), and 5.8% (Ramucirumab) of all patients treated with sorafenib were demonstrated to qualify for second-line treatment with these drugs after sorafenib failure [98].

Immunotherapy has emerged as a promising and transformative avenue in the nonsurgical management of HCC. Notably, several landmark clinical trials have demonstrated the efficacy and potential of immune checkpoint inhibitors in the treatment of advanced HCC. The IMbrave150 trial, a phase III study, established the combination of Atezolizumab and Bevacizumab as a first-line treatment option for unresectable HCC, showcasing significantly improved overall survival and progression-free survival compared to sorafenib [13]. The phase III HIMALAYA trial, which evaluated the combination of anti-PD-L1 Durvalumab and anti-CTLA4 Tremelimumab versus sorafenib, successfully met its primary endpoint of improving overall survival [14]. Thus, both treatment regimens were approved by the FDA as first-line treatment for unresectable HCC. Subgroup analyses of these landmark trials demonstrated a significant advantage of Atezolizumab/Bevacizumab in viral hepatitis, hepatitis B and C [13]. STRIDE demonstrated good efficacy in patients with HCC with nonviral etiology but weak advantages in viral hepatitis [14]. In addition, Nivolumab and Pembrolizumab were approved by the FDA for second-line monotherapy after sorafenib failure but not in Europe or Japan. However, after approval by the FDA, CheckMate 459 and KEYNOTE-240 trials failed to further support a substantial role of either drug in first- or second-line treatment at least in monotherapy [99, 100]. Just recently, Nivolumab and Ipilimumab met their primary endpoint of improving OS as a first-line setting [101].

Immune-related adverse events were generally manageable. Few patients have severe adverse events such as immune therapy-mediated hepatopathies or diarrhea. These adverse events may require discontinuation or immune suppressive treatment and were so far considered a disadvantage [13, 14, 102]. Just recently, subgroup analysis of these patients from the HIMALAYA trial suggested that patients suffering from those immune-mediated adverse events may in fact have a better outcome – an aspect that certainly needs further evaluation.

A proof-of-concept study clearly showed that Atezolizumab plus Bevacizumab can achieve complete response by combining locoregional therapy (ABC conversion) [103].

Tumor Heterogeneity

For a long time, tumor heterogeneity has been acknowledged as key issue in liver cancer biology, diagnostics, and targeted therapy. Over 2 decades, genetic signatures failed to make it into clinical routine decision making. A major problem in validating such signatures has always been tumor heterogeneity. Also, immunotherapeutic approaches, particularly immune checkpoint inhibitors, have demonstrated remarkable responses in a subset of HCC patients. However, there is significant heterogeneity in patient responses to immunotherapy. Some patients show durable responses, while others exhibit minimal or no benefit. In addition, with the setbacks observed in the LEAP-002 [104] and COSMIC-312 [105] trials, there has been a renewed focus on investigating the substantial differences in therapeutic efficacy of various drug combinations in targeted immunotherapies for unresectable HCC. Unraveling the factors influencing (immunotherapy) response heterogeneity, such as tumor microenvironment characteristics and immune cell infiltrates, is essential to identify patients who are most likely to benefit from immunotherapy and to develop combination strategies to enhance treatment efficacy.

Personalized and Precision Medicine, Definition of HCC Subgroups

Large sequencing efforts around the globe demonstrated a robust mutational spectrum of HCC [106]. Thus, the future of targeted HCC treatment may lie in personalized and precision medicine approaches. By utilizing advanced technologies like genomics, transcriptomics, and proteomics, researchers can identify specific genetic alterations and molecular pathways driving HCC growth. This knowledge will enable the development of targeted therapies tailored to individual patients’ unique tumor profiles, maximizing treatment efficacy while minimizing adverse effects. Integrating patient-specific biomarkers into clinical decision making will revolutionize HCC management, providing more effective and personalized treatment options.

Awareness, Early Detection, and Surveillance Gaps

Despite the importance of early detection in improving HCC outcomes, challenges persist in implementing effective surveillance programs, especially in high-risk populations. Limited awareness among at-risk individuals, the lack of standardized surveillance guidelines, and the variable sensitivity of available screening tools can result in delays in HCC diagnosis. Enhancing public awareness, promoting adherence to surveillance guidelines, and investigating novel biomarkers for early detection are key areas of focus to address this challenge. Also, advancements in liquid biopsies, molecular imaging, and artificial intelligence-based algorithms for early HCC detection hold promise. Integrating these technologies into routine clinical practice will enable earlier diagnosis and intervention, increasing the likelihood of curative treatments and improved patient survival, which is already achieved in Japan [107]. In addition to AFP, measurement of PIVKA-II and AFP-L3 must play a very important role as revealed in Japan [103, 108, 109].

Overcoming Cirrhosis-Related Limitations

The majority of HCC cases are associated with underlying liver cirrhosis, which presents additional challenges in HCC treatment. Cirrhosis can impact treatment decisions, limit treatment options, and increase the risk of complications. Addressing cirrhosis-related limitations requires a comprehensive approach, including managing liver function, reducing risk factors, and selecting appropriate treatment modalities tailored to each patient's individual circumstances.

The management of HCC has witnessed remarkable advancements in the past 4 decades, with improved screening, surgical interventions, targeted therapies, and immunotherapeutic approaches. A comprehensive and multidisciplinary approach is crucial for effective HCC management. Continued research and clinical trials are imperative to further enhance treatment options and ultimately reduce the global burden of this devastating disease.

The authors have no conflicts of interest to declare.

AT received grants from the Sino-German Center for Research Promotion (Grant Nos. GZ-1546 and C-0012), the State Ministry of Baden-Wuerttemberg for Sciences, Research and Arts supporting the Clinical Cooperation Unit Healthy Metabolism at the Center for Preventive Medicine and Digital Health (grant identifier: CCU Healthy Metabolism), the Foundation for Biomedical Alcohol Research (Grant identifier: N/A), and the Baden-Wuerttemberg Center for Digital Early Disease Detection and Prevention (Grant identifier: BW-ZDFP).

Conceptualization: Y.Q. and A.T. Data curation: Y.Q., J.D., and I.R. Supervision: A.T., M.K., C.R., E.R., and M.E. Writing – original draft: A.T., M.K., Y.Q., J.D., and I.R. Writing – review and editing: A.T., M.K., C.R., E.R., and M.E.

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