Immunotherapy for virus-related hepatocellular carcinoma: recent progress and future directions.

1.
Introduction
Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, accounting for approximately 80% of cases, and is one of the leading causes of cancer-related deaths worldwide. According to recent statistics, liver cancer ranks sixth in global cancer incidence and third in cancer-related mortality, with new cases projected to exceed one million by 2025 [1]. The development of HCC is associated with multiple factors, including viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, and aflatoxin exposure. Among these, chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) remains the most critical risk factor. Globally, HBV accounts for about 39% of all HCC cases. In HBV-endemic regions such as China, South Korea, and Japan, this proportion is even higher; in China, up to 92.05% of HCC patients have HBV infection. In contrast, in Western countries, HCV infection is the predominant cause of HCC. Although the incidence of HCV-related HCC has declined following the widespread use of direct-acting antivirals (DAAs), it continues to pose a major public health burden [2].
For early-stage HCC patients, curative surgical treatments such as hepatectomy, liver transplantation, and ablation remain effective. For most patients with intermediate-stage HCC, transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are recommended [3]. However, the majority of patients are diagnosed at advanced stages, when curative surgery is not feasible. For over a decade, sorafenib was the only systemic therapy available for advanced HCC, but its efficacy was limited, with a median overall survival (OS) of just 14.5 months [4]. The advent of tumor immunology and immunotherapy has fundamentally transformed the treatment landscape of HCC. Recent advances in tumor immunology and immunotherapy have transformed the treatment landscape of HCC. The introduction of immune checkpoint inhibitors (ICIs) marked a major milestone, and ICI-based combination therapies have further broadened treatment options [5].
Virus-related HCC exhibits unique features in immunotherapy. HBV and HCV infections are not only etiological factors but also profoundly shape the hepatic immune microenvironment. Moreover, antiviral treatment status, viral load, and viral genotype may critically influence the efficacy of immunotherapy [6,7]. Therefore, a thorough understanding of the immunological characteristics of virus-related HCC and the design of individualized therapeutic strategies are essential to improving treatment outcomes.
This review provides a comprehensive overview of recent advances in immunotherapy for HCC, with a focus on immune checkpoint inhibitors, combination strategies, and neoadjuvant immunotherapy. Special emphasis is placed on the unique aspects of immunotherapy in virus-related HCC, including the impact of virological factors on therapeutic efficacy and the interactions between antiviral and immune therapies.

2.
Application of immune checkpoint inhibitors in the treatment of HCC
2.1.
Mechanism of PD-1/PD-L1 inhibition
Programmed cell death protein 1 (PD-1) and its ligand PD-L1 are pivotal immune checkpoint molecules. PD-1 is primarily expressed on activated T cells, B cells, and natural killer (NK) cells, while PD-L1 is broadly expressed on tumor cells, antigen-presenting cells, and other immune cells. The binding of PD-1 to PD-L1 transmits inhibitory signals, leading to suppression of T-cell function, reduced proliferation, and increased apoptosis, which is a key mechanism of tumor immune evasion.Under physiological conditions, the liver maintains a state of immune tolerance to prevent excessive immune responses against nonpathogenic antigens from the gut, while simultaneously preserving rapid responses against infections and tumors. The liver harbors a diverse array of immune cells, including resident macrophages (Kupffer cells), dendritic cells, and NK cells, which play crucial roles in both immune homeostasis and antitumor immunity. This complex immunoregulatory system is intricately involved in the development of HCC and provides the theoretical basis for immunotherapy. Studies have shown that in HCC, PD-L1 expression is closely associated with tumor aggressiveness and prognosis. Patients with high PD-L1 expression tend to have worse outcomes but may respond better to PD-1/PD-L1 blockade therapy [8]. PD-1/PD-L1 inhibitors restore T-cell antitumor activity by blocking this inhibitory pathway, thereby enhancing immune recognition and cytotoxicity against tumor cells [9]. The mechanisms of immune checkpoint regulation in HCC are illustrated in Figure 1.

2.2.
Clinical studies of PD-1/PD-L1 inhibitor monotherapy
Nivolumab was the first PD-1 inhibitor to demonstrate clinical efficacy in HCC. In the CheckMate 040 study, nivolumab was used as second-line therapy in advanced HCC patients who had failed sorafenib. The results showed an objective response rate (ORR) of 20%, a disease control rate (DCR) of 64%, and a median OS of 15.6 months, with manageable safety [10]. Based on these findings, the U.S. FDA approved nivolumab in 2017 for patients with advanced HCC previously treated with sorafenib. Long-term follow-up of CheckMate 040 confirmed durable clinical benefit and consistent safety across patient subgroups, including those with Child-Pugh B liver function [8,11]. However, the CheckMate 459 trial, comparing nivolumab with sorafenib as first-line therapy, showed only a numerical OS advantage (16.4 vs. 14.7 months) that did not reach statistical significance [12].
Pembrolizumab is another widely studied PD-1 inhibitor. In the KEYNOTE-224 trial, pembrolizumab achieved an ORR of 17% and a median OS of 12.9 months in sorafenib-pretreated advanced HCC patients [13]. A subsequent phase III trial in Asian patients showed an ORR of 12.7%, median OS of 14.6 months, and median progression-free survival (PFS) of 2.6 months [14]. The KEYNOTE-240 study further evaluated pembrolizumab as second-line therapy; although trends toward improved OS and PFS were observed, the predefined statistical thresholds were not met [15].
Other ICIs, including atezolizumab, durvalumab, and camrelizumab, have also been tested as monotherapy in HCC, generally yielding ORRs of 15–20%. These results suggest that while ICI monotherapy provides clinical benefit, its efficacy in HCC is limited [16]. The key clinical trials of immune checkpoint inhibitor monotherapy in HCC are summarized in Table 1.

2.3.
Exploration of combination therapy strategies
The heterogeneity of HCC and the complexity of its tumor microenvironment often limit the efficacy of single-agent therapies. Combination strategies that integrate different therapeutic modalities can achieve synergistic effects and improve treatment outcomes.
2.3.1.
Immunotherapy Combined with targeted therapy
2.3.1.1.
Immunotherapy Combined with anti-angiogenic therapy
In 2020, the IMbrave150 trial compared atezolizumab plus bevacizumab with sorafenib in unresectable HCC patients. The combination demonstrated significant superiority over sorafenib in all primary endpoints: overall survival (OS) (19.2 vs. 13.4 months, HR = 0.66, p < 0.001), progression-free survival (PFS) (6.9 vs. 4.3 months, HR = 0.65, p < 0.001), and objective response rate (ORR) (30% vs. 11%, p < 0.001) [16]. Notably, the PFS with atezolizumab plus bevacizumab exceeded that of atezolizumab monotherapy. The success of this regimen is based on the synergistic mechanisms of ICIs and anti-angiogenic therapy. Bevacizumab blocks the VEGF pathway, thereby inhibiting angiogenesis, normalizing tumor vasculature, and promoting immune cell infiltration. It also reduces immunosuppressive cell infiltration, further enhancing antitumor immunity [17,18]. Based on these results, the FDA approved atezolizumab plus bevacizumab in 2020 as first-line treatment for unresectable HCC, which has since become the global standard of care.

2.3.1.2.
Immunotherapy Combined with multikinase inhibitors (MKIs)
Multikinase inhibitors (MKIs), such as sorafenib, lenvatinib, and regorafenib, play an important role in HCC treatment by targeting multiple kinases involved in angiogenesis and tumor proliferation. Combining MKIs with ICIs has a strong theoretical basis: PD-1/PD-L1 blockade restores T-cell antitumor activity, while MKIs not only inhibit tumor growth and angiogenesis but also modulate the tumor microenvironment by reducing immunosuppressive cell infiltration, thereby augmenting T-cell function [19]. The KEYNOTE-524 trial evaluated pembrolizumab plus lenvatinib in advanced HCC, reporting an impressive ORR of 46% and median PFS of 9.3 months, outperforming historical controls [20]. However, the subsequent phase III LEAP-002 trial, which compared lenvatinib plus pembrolizumab versus lenvatinib monotherapy as first-line treatment, failed to meet its dual primary endpoints. Although the median OS (21.2 vs. 19.0 months, HR = 0.84, p = 0.0227) and PFS (8.2 vs. 8.0 months, HR = 0.87, p = 0.0466) were numerically longer in the combination arm, the results did not reach the pre-specified statistical significance threshold [21]. This highlights the challenges in translating phase Ib results to large-scale randomized trials.
Conversely, the combination of camrelizumab (an anti-PD-1 antibody) and rivoceranib (a VEGFR-2 TKI) demonstrated positive results in a global phase III trial (CARES-310). The combination provided statistically significant superiority over sorafenib for both median OS (22.1 vs. 15.2 months, HR = 0.62) and PFS (5.6 vs. 3.7 months, HR = 0.52) [22]. Although associated with a higher rate of treatment-related adverse events (80.9% vs. 52.4%), this regimen represents a potent new first-line option.

2.3.1.3.
Immunotherapy Combined with other targeted agents
Beyond anti-angiogenic agents and MKIs, ICIs are being explored in combination with other targeted therapies. The COSMIC-312 phase III trial evaluated cabozantinib plus atezolizumab versus sorafenib. While the combination significantly improved PFS (6.8 vs. 4.2 months, HR = 0.63), it failed to demonstrate a significant improvement in OS (15.4 vs. 15.5 months, HR = 0.90) [23]. These mixed results suggest that PFS benefits do not always translate to survival advantages in HCC combination therapies. Other combinations involving mTOR inhibitors, CDK4/6 inhibitors, and PARP inhibitors remain under clinical investigation to further enhance tumor immunogenicity and sensitivity to ICIs. For example: mTOR inhibitors suppress tumor cell growth and metabolism, potentially enhancing the efficacy of ICIs [24]. CDK4/6 inhibitors induce tumor cell senescence, modulate the immune microenvironment, and restore tumor immunogenicity, synergizing with immunotherapy [25]. PARP inhibitors induce DNA damage accumulation in homologous recombination-deficient cells, thereby increasing tumor immunogenicity and sensitivity to ICIs [26]. These novel combinations hold promise but remain under clinical investigation.

2.3.2.
Immunotherapy combined with locoregional therapies
2.3.2.1.
Immunotherapy plus transarterial chemoembolization (TACE)
TACE is the standard therapy for intermediate-stage HCC. In addition to inducing local tumor necrosis via arterial embolization and chemotherapy, TACE also triggers systemic immune responses. Tumor cell death releases antigens that activate antigen-presenting cells and stimulate T-cell priming, a phenomenon often described as a “vaccine effect” [27,28]. A nationwide multicenter retrospective study of 1,244 advanced HCC patients compared TACE + ICI + VEGF inhibitor with ICI + VEGF inhibitor. Results showed significantly improved median OS (22.6 vs. 15.9 months), longer PFS (9.9 vs. 7.4 months), and higher ORR (41.2% vs. 22.9%) in the triple combination group [29]. Similar studies have confirmed these findings, suggesting that TACE-ICI combinations enhance local control and extend survival [30].

2.3.2.2.
Immunotherapy plus radiotherapy
Radiotherapy is not routinely applied in HCC but is used in locally advanced or metastatic cases. Emerging evidence indicates that radiotherapy synergizes with ICIs. Mechanistically, radiotherapy increases tumor antigen release, upregulates MHC and costimulatory molecules on tumor cells, and remodels the tumor microenvironment by reducing immunosuppressive cell infiltration [31,32]. Stereotactic body radiotherapy (SBRT) combined with ICIs has shown encouraging outcomes, not only enhancing local control but also inducing abscopal effects, where untreated lesions also regress [33,34].

2.3.2.3.
Immunotherapy plus ablation
Ablation techniques such as radiofrequency ablation (RFA) and microwave ablation (MWA) are widely used in early-stage HCC. Besides direct cytotoxicity, ablation reshapes the hepatic immune microenvironment by promoting immune activation. However, incomplete ablation may foster an immunosuppressive milieu that facilitates recurrence. ICIs can counteract this by restoring systemic immune surveillance [35]. Clinical studies suggest that ablation combined with ICIs reduces local recurrence rates and potentially improves long-term survival, making it an attractive strategy for early-stage HCC [36].

2.3.3.
Dual immune checkpoint blockade
PD-1/PD-L1 and CTLA-4 are two critical checkpoints acting at different stages of T-cell activation. CTLA-4 functions during early T-cell priming by competing with CD28 for CD80/86 binding, while PD-1 primarily suppresses effector T-cell activity. Dual blockade provides complementary enhancement of antitumor immunity [37]. The HIMALAYA trial validated this approach: the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab) demonstrated superiority over sorafenib with a median OS of 16.4 months versus 13.8 months (HR = 0.78, 96% CI 0.65–0.93). The 4-year OS rate was notably higher at 25.2% compared with 15.2% in the sorafenib arm [38]. This led to FDA approval of the durvalumab–tremelimumab combination in 2022 for unresectable HCC.Similarly, the combination of nivolumab plus ipilimumab has shown promise. In the CheckMate 040 cohort 4, this dual regimen achieved an ORR of 32% and a median OS of 22.8 months in sorafenib-treated patients, leading to FDA accelerated approval in the second-line setting [39]. The confirmatory phase III CheckMate 9DW trial is currently ongoing to evaluate this combination against investigator’s choice of sorafenib or lenvatinib in the first-line setting.
Other checkpoints, such as TIM-3, LAG-3, and TIGIT, are being investigated as potential targets. Preclinical and early clinical studies suggest that simultaneous blockade of multiple inhibitory pathways may further boost antitumor immunity [40,41]. However, dual or multiple checkpoint blockade carries higher toxicity risks. In HIMALAYA, grade 3–4 adverse events occurred in ∼50% of patients, underscoring the need for careful patient selection. The major combination immunotherapy strategies and their clinical outcomes are presented in Table 2.

2.4.
Neoadjuvant immunotherapy
Surgical resection remains the primary curative option for early-stage HCC, but only 10–30% of patients are resectable at diagnosis. Even after curative resection, recurrence rates reach up to 70% within five years, mostly intrahepatic, due to micrometastases or de novo tumors [34]. Neoadjuvant immunotherapy – administered prior to surgery – aims to shrink tumors, facilitate resection, and eliminate micrometastases. Recent studies show that ICIs used in the neoadjuvant setting increase pathological complete response rates and reduce recurrence risk [42]. Mechanisms include enhanced antigen release, dendritic cell activation, T-cell clonal expansion, and long-term immune memory formation [34]. Collectively, these findings highlight the promise of neoadjuvant immunotherapy in early-stage HCC.The comprehensive treatment algorithm integrating immunotherapy across different BCLC stages is presented in Figure 2.

3.
Immunotherapy in virus-related HCC
Chronic viral hepatitis is not only a major etiological factor of HCC but also profoundly influences its immune microenvironment and response to therapy. Both HBV and HCV infections are characterized by persistent antigen stimulation, immune tolerance, and varying degrees of immune dysfunction, which affect the efficacy and safety of immune checkpoint inhibitors (ICIs). The distinct immunological features of HBV- and HCV-related HCC are compared in Table 3. A management algorithm for immunotherapy in virus-related HCC is outlined in Figure 3.
3.1.
HBV-related HCC
3.1.1.
Immune characteristics of HBV infection
HBV infection is strongly associated with HCC, and chronic HBV infection profoundly alters the hepatic immune microenvironment, creating unique conditions for both carcinogenesis and immunotherapy. Persistent immune activation and inflammation are central to HBV-driven hepatocarcinogenesis. HBV proteins, particularly HBsAg and HBeAg, provide continuous antigenic stimulation, leading to chronic activation and eventual exhaustion of HBV-specific CD8+ T cells. This exhausted phenotype is characterized by high expression of inhibitory receptors such as PD-1, TOX, TIM-3, and LAG-3, and loss of effector function [6,43,44]. HBV also directly modulates liver immune cell function. NK cells, enriched in the HBV-infected liver, show impaired cytotoxic activity, with reduced production of IFN-γ and TNF-α and dysregulated expression of granzyme B and perforin [45]. Additionally, HBV suppresses dendritic cell maturation and antigen presentation, while modulating helper T-cell responses [46]. These immune alterations contribute not only to viral persistence but also to impaired anti-tumor immunity.
A crucial component of this altered landscape is the population of CD4+CD25+Foxp3+ regulatory T cells (Tregs). Tregs play a fundamental immunosuppressive role in maintaining immune homeostasis and preventing autoimmunity. However, in the context of HCC, tumor cells actively recruit Tregs to the tumor microenvironment to evade immune surveillance. Chronic HBV infection is characterized by an abundant accumulation of Tregs in the liver, which promotes immune tolerance to viral antigens while concurrently suppressing anti-tumor immune responses [46,47]. This sharply contrasts with autoimmune liver diseases, such as autoimmune hepatitis, which are often associated with numerical and functional Treg defects – potentially contributing to the lower incidence of HCC observed in these conditions [47]. The tolerogenic nature of the liver is reinforced in chronic HBV infection, with increased immunosuppressive cytokines, regulatory T-cell expansion, and accumulation of myeloid-derived suppressor cells (MDSCs). Although this environment mitigates hepatic inflammation, it also limits anti-tumor immune responses.

3.1.2.
Impact of HBV DNA levels on immunotherapy
HBV DNA levels, a key indicator of viral replication, are an important determinant of immunotherapy outcomes. Recent studies suggest that elevated HBV DNA during immune checkpoint inhibitor (ICI) therapy correlates with tumor progression and reduced survival, independent of baseline viral load [48]. Another retrospective study found no significant difference in OS or PFS between high and low baseline HBV DNA groups receiving combined antiviral and immunotherapy. However, patients who received antiviral therapy, regardless of HBV DNA levels, demonstrated significantly improved OS compared with untreated patients (20.6 vs. 11.1 months, p = 0.020), and antiviral therapy was identified as an independent protective factor for OS [49]. These findings indicate that effective antiviral therapy may enhance immunotherapy efficacy. Potential mechanisms include stabilization of liver function, restoration of CD8+ T-cell effector activity, modulation of the tumor microenvironment, and reduced recurrence rates [49].

3.1.3.
Interaction between antiviral and immunotherapy
Antiviral therapy plays a pivotal role in HBV-related HCC management during immunotherapy. Nucleos(t)ide analogues (NAs), the standard of care for HBV infection, inhibit reverse transcriptase activity and viral replication. In HBV-related HCC, antiviral therapy may not only suppress viral replication but also enhance immunotherapy efficacy by reducing antigen load, alleviating T-cell exhaustion, decreasing hepatic inflammation, and mitigating immunosuppressive signals [50]. Studies confirm that effective antiviral therapy improves the immune milieu by reducing fibrosis and inflammation, thereby enhancing anti-tumor responses when combined with ICIs [50,51]. Furthermore, antiviral therapy reduces the risk of HBV reactivation, a major immune-related adverse event during ICI therapy, underscoring the necessity of prophylactic antivirals in HBV-positive patients [52]. Immunotherapy may also support viral control: blockade of the PD-1/PD-L1 axis not only restores anti-tumor immunity but also reinvigorates antiviral T-cell responses, potentially suppressing HBV replication [52].

3.2.
HCV-related HCC and immunotherapy
3.2.1.
Immunological features of HCV infection
HCV infection differs substantially from HBV in its immunological profile. As an RNA virus that does not integrate into the host genome, HCV evades immune clearance through multiple mechanisms. Chronic HCV infection induces T-cell exhaustion and functional impairment, but via distinct pathways compared with HBV [7]. HCV core and non-structural proteins inhibit dendritic cell function, suppress antiviral T-cell responses, and promote regulatory T-cell expansion along with immunosuppressive cytokine secretion, thereby supporting persistent infection. Moreover, HCV infects both hepatocytes and hematopoietic cells, disrupting multiple immune cell subsets by interfering with promoter and signaling proteins essential for viral clearance[53]. Unlike HBV, HCV infection has higher rates of spontaneous and treatment-induced clearance. Direct-acting antivirals (DAAs) can achieve viral eradication in >95% of cases, providing a distinct therapeutic background for immunotherapy in HCV-related HCC.

3.2.2.
Impact of DAA therapy on immunotherapy
DAA therapy rapidly and effectively clears HCV, but its impact on immune function is complex. While viral clearance reduces antigen burden, it may also dampen HCV-specific CD8+ T-cell cytotoxicity, beginning early in treatment and persisting after completion. Downregulation of antigen processing and presentation, as well as complement cascade suppression, have been observed post-DAA therapy [53]. Thus, immune recovery may be delayed, leaving residual immune dysfunction. Interestingly, recent studies indicate that ICIs may inhibit HCV replication and promote viral clearance [54], suggesting dual anti-tumor and antiviral effects in HCV-related HCC. However, other reports indicate an increased risk of HCC occurrence shortly after DAA therapy, possibly related to immune reconstitution dynamics [55]. This highlights the importance of careful timing when combining DAAs with immunotherapy.

3.2.3.
Safety of immunotherapy in HCV-related HCC
The safety profile of ICIs in HCV-related HCC is generally favorable. Unlike HBV, HCV reactivation is rare during immunotherapy because the virus does not integrate into the host genome [56]. Multiple studies have shown that the incidence and severity of immune-related adverse events in HCV-infected patients are comparable to those in uninfected patients[13], supporting the safety of ICIs in this population.

3.3.
Safety profile and immune-related adverse events in virus-related HCC
While ICIs have revolutionized HCC treatment, they are associated with a unique spectrum of side effects known as immune-related adverse events (irAEs). The safety profile in virus-related HCC is generally consistent with non-viral etiologies, but specific considerations apply. The reactivation of latent immune responses can lead to inflammatory damage in healthy tissues. Common irAEs include dermatitis, colitis, hepatitis, and endocrinopathies. Importantly, in virus-related HCC, the liver is already compromised; therefore, differentiating between immune-mediated hepatitis and viral flares or tumor progression is critical.
Furthermore, while less frequent, hematological immune-related adverse events (hem-irAEs) such as immune thrombocytopenia, anemia, and neutropenia have been reported and can be life-threatening if not recognized early. A comprehensive review highlighted that although hem-irAEs are rare, they require vigilant monitoring of blood counts throughout ICI therapy[57]. The pathogenesis of these events may involve autoantibody production or T-cell mediated destruction of hematopoietic cells, mechanisms that could be influenced by the chronic inflammatory state induced by viral hepatitis. For instance, a recent case report highlighted a patient with HCC treated with atezolizumab who developed pure red cell aplasia (PRCA) driven by Parvovirus B19 infection, emphasizing the critical need to distinguish between direct drug-induced toxicity and viral-associated etiologies [58]. Therefore, vigilant monitoring and a thorough differential diagnosis are essential.

4.
Optimization strategies for immunotherapy in virus-associated HCC
The efficacy of immunotherapy in HCC is still limited to a subset of patients, highlighting the need for optimization strategies. For virus-associated HCC, these strategies involve personalizing treatment based on predictive biomarkers, developing rational combination therapies, and integrating antiviral treatment.
4.1.
Biomarker-guided patient selection
Identifying reliable biomarkers is crucial for selecting patients who are most likely to benefit from immunotherapy and for guiding combination strategies. While PD-L1 expression has been an inconsistent predictor in HCC, other potential biomarkers are under investigation [59].
4.1.1.
Tumor mutational burden (TMB) and microsatellite instability (MSI)
High TMB and MSI-High status are established predictors of response to ICIs in various cancers. However, their prevalence in HCC is low, limiting their utility as widespread biomarkers in this disease [60].

4.1.2.
Inflammatory gene signatures
Transcriptomic profiling of the TME can identify inflammatory signatures associated with response to ICIs. A T-cell-inflamed gene expression profile has been linked to better outcomes with pembrolizumab in HCC.

4.1.3.
Circulating biomarkers
Liquid biopsies offer a non-invasive approach to monitor treatment response and resistance. Circulating tumor DNA (ctDNA), as well as peripheral blood immune cells, are being explored as potential biomarkers. For example, a low baseline neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been associated with better survival in HCC patients treated with ICIs [61]. Serum levels of alpha-fetoprotein (AFP) have also been correlated with immunotherapy outcomes.

4.1.4.
Gut microbiome
The composition of the gut microbiome has been shown to influence systemic immune responses and the efficacy of ICIs in several cancers. Modulating the gut microbiome could be a potential strategy to enhance immunotherapy response in HCC, although this is still in the exploratory phase.

4.2.
Rational combination therapies
Combining ICIs with other therapeutic modalities is a key strategy to improve response rates. The goal is often to convert “immune-cold” tumors, which are poorly infiltrated by T cells, into “immune-hot” tumors that are more responsive to immunotherapy.
4.2.1.
Combination with anti-angiogenic agents
As demonstrated by the success of the atezolizumab plus bevacizumab regimen, combining ICIs with anti-VEGF therapy is a highly effective strategy. Anti-angiogenic agents not only inhibit tumor vascularization but also modulate the TME by promoting T-cell infiltration and reducing the number of immunosuppressive cells[62].

4.2.2.
Combination with tyrosine kinase inhibitors (TKIs)
TKIs like lenvatinib and cabozantinib have immunomodulatory effects in addition to their anti-proliferative and anti-angiogenic properties. Combining them with ICIs can create a synergistic anti-tumor effect, as seen with the lenvatinib plus pembrolizumab combination.

4.2.3.
Combination with locoregional therapies
Integrating ICIs with locoregional therapies such as TACE, radiotherapy, or ablation can enhance systemic anti-tumor immunity. These therapies can induce immunogenic cell death, leading to the release of tumor antigens and the priming of a T-cell response (an “abscopal effect”), which can be amplified by ICIs [63].

4.3.
Integration of antiviral therapy
For patients with virus-associated HCC, managing the underlying viral infection is a critical component of the overall treatment strategy [64]. As discussed previously, effective antiviral therapy for HBV and HCV can improve liver function, prevent viral reactivation, and potentially enhance the efficacy of immunotherapy. Therefore, close collaboration between oncologists and hepatologists is essential to ensure that patients receive appropriate antiviral management before, during, and after immunotherapy.
In HBV-related HCC, antiviral therapy should ideally precede immunotherapy, with the goal of achieving undetectable HBV DNA levels. First-line nucleos(t)ide analogues include entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide, and amenamevir; the latter two may be preferred in patients with renal impairment or bone density loss. For patients with HCV-related HCC, it is theoretically preferable to complete the DAA regimen before initiating immunotherapy, with an appropriate interval afterward to allow immune recovery. However, HCC often progresses rapidly, leaving only a narrow therapeutic window. In clinical practice, a balance must be struck between viral eradication and tumor control, and the optimal treatment sequence should be individualized based on tumor progression rate, liver function reserve, and overall disease status.
Beyond standard antiviral therapy, modulation of the immune microenvironment may further improve outcomes. Interferons exert both antiviral and immunostimulatory effects, and sequential therapy with pegylated interferon α-2b plus anti-PD-1 antibodies has demonstrated encouraging efficacy in advanced HCC [65]. Additional strategies, including adjuvants, cytokines, and adoptive cell therapies, are under investigation to restore anti-tumor immunity and overcome virus-induced immunosuppression.
Management should be individualized according to viral status, liver function, tumor burden, and immune competence. Patients with high HBV DNA levels require intensified antiviral therapy before immunotherapy initiation, whereas those with well-controlled viral loads may proceed directly. Continuous monitoring of virological and immunological markers, tumor response, and treatment-related adverse events is indispensable throughout the course of therapy.Optimization strategies for immunotherapy in virus-related HCC are summarized in Table 4.

5.
Future directions and emerging therapies
Immunotherapy for hepatocellular carcinoma (HCC) has made significant strides, moving from preclinical research to clinical application and offering new hope for patients. Virus-associated HCC poses unique challenges, as chronic HBV or HCV infection alters the hepatic immune microenvironment, leading to immune exhaustion and suppression that may limit treatment efficacy. Combination strategies, including immunotherapy with targeted or locoregional therapies, show synergistic potential. Multi-immune checkpoint inhibition and personalized approaches further enhance treatment prospects, though balancing efficacy and toxicity remains crucial. Challenges such as limited response rates, resistance mechanisms, biomarker scarcity, safety concerns, and high costs persist. Advances in next-generation checkpoint inhibitors, bispecific antibodies, ADCs, and novel tumor vaccines, alongside precision medicine approaches, are expected to expand therapeutic options.
Future directions for immunotherapy in virus-associated HCC focus on enhancing efficacy and personalization. Efforts include targeting novel immune checkpoints such as TIM-3, LAG-3, TIGIT, and VISTA, as well as using agonists for co-stimulatory molecules like OX40 and 4-1BB to boost T-cell activity. Cellular therapies, including CAR-T, TCR-engineered T cells, and tumor-infiltrating lymphocytes (TILs), are being adapted for HCC by targeting tumor-associated antigens such as GPC3. Therapeutic vaccines, targeting viral antigens (HBV/HCV) or patient-specific neoantigens, aim to generate robust tumor-specific T-cell responses. Ultimately, integrating multi-omics, clinical, and imaging data will enable personalized treatment selection, optimizing efficacy while minimizing toxicity. With these advances, HCC immunotherapy may transform the disease from fatal to manageable, improving patient outcomes and quality of life.
In conclusion, the field of immunotherapy for HCC is rapidly evolving. Continued research into the complex biology of virus-associated HCC, the development of novel therapeutic strategies, and the identification of robust predictive biomarkers will be essential to further improve outcomes for patients with this challenging disease.

6.
Conclusion
Immunotherapy has fundamentally reshaped the treatment paradigm of hepatocellular carcinoma (HCC), providing durable clinical benefit for a subset of patients. Virus-related HCC presents unique immunological characteristics, as chronic HBV and HCV infections induce immune exhaustion, shape a tolerogenic microenvironment, and modulate treatment responses. Current evidence highlights the importance of integrating antiviral therapy with immune checkpoint inhibitors to optimize efficacy and minimize risks, particularly HBV reactivation. Combination strategies with targeted agents, locoregional therapies, and dual checkpoint blockade have further improved outcomes, though challenges remain in patient selection, biomarker validation, resistance mechanisms, and toxicity management.
Looking forward, advances in next-generation immune checkpoints, bispecific antibodies, cellular therapies, and therapeutic vaccines hold great promise to expand therapeutic options. For virus-associated HCC, individualized treatment strategies that incorporate virological status, immune biomarkers, and patient-specific clinical factors will be essential. Ultimately, a deeper understanding of virus–immune–tumor interactions will enable more precise, effective, and safe immunotherapy approaches, transforming HCC from a fatal disease into a manageable condition with improved survival and quality of life.