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

Sep 30, 2026

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death globally, driven largely by chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Persistent viral infection fuels carcinogenesis and reorganizes the hepatic immune microenvironment, thereby altering both the efficacy and safety profile of immunotherapy. Immune checkpoint inhibitors (ICIs), especially PD-1/PD-L1 blockade, have advanced systemic treatment for advanced HCC. Integrated antiviral management and combination regimens improve responses while mitigating risks such as HBV reactivation. Future directions emphasize next-generation checkpoints, bispecific antibodies, cellular therapies, tumor vaccines, biomarker-guided personalized selection, and multi-omics-driven optimization to overcome heterogeneity, resistance, and toxicity.

LanguageEnglish

CategoryHealthcare

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Pages15

Reading Time38 min

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Abstract

1. Introduction

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AnnAls of Medicine 2026, Vol. 58, no. 1, 2607229 [https://doi.org/10.1080/07853890.2025.2607229](https://doi.org/10.1080/07853890.2025.2607229) REVIEW ARTICLE Immunotherapy for virus-related hepatocellular carcinoma: recent progress and future directions Ruijuan Song, Mingyuan Li, Shengqiang Tang and Guoliang Zhang Anhui Hospital of shuguang Hospital Affiliated to shanghai University of Traditional chinese Medicine, Hefei, Anhui Province, china ABSTRACT Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remaining the predominant etiological factors. Chronic viral infection not only drives carcinogenesis but also reshapes the hepatic immune microenvironment, profoundly influencing the efficacy and safety of immunotherapy. Recent advances: Immune checkpoint inhibitors (ICIs) have revolutionized systemic therapy for advanced HCC, with agents targeting PD-1/PD-L1 demonstrating clinical benefit. Combination strategies – such as ICIs with anti-angiogenic therapies, multikinase inhibitors, or locoregional treatments – have shown synergistic efficacy and are now standard of care in certain settings. For virus-related HCC, antiviral therapy improves immune responsiveness and reduces risks such as HBV reactivation, underscoring the need for integrated management. Future perspectives: Emerging therapeutic approaches include next-generation immune checkpoints (e.g. TIM-3, LAG-3, TIGIT), bispecific antibodies, cellular therapies (CAR-T, TCR-T, TILs), and tumor vaccines targeting viral or tumor-associated antigens. Advances in biomarker discovery, including circulating tumor DNA, immune signatures, and microbiome modulation, are expected to guide personalized treatment. Integration of multi-omics and clinical data will further refine patient selection and optimize treatment sequencing. Conclusion: Immunotherapy offers new hope for patients with virus-related HCC, but challenges remain in response heterogeneity, resistance, and toxicity. Individualized strategies that combine immunotherapy with effective antiviral management and biomarker-|guided patient selection are essential. Continued translational and clinical research into virus–immune–tumor interactions will enable safer, more effective, and more durable treatment outcomes, ultimately transforming HCC into a more manageable disease. 1. Introduction ARTICLE HISTORY Received 8 October 2025 Revised 12 December 2025 Accepted 15 December 2025 KEYWORDS Hepatocellular carcinoma; immunotherapy; immune checkpoint inhibitors; hepatitis B virus; hepatitis C virus; combination therapy; biomarkers; tumor microenvironment 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] . CONTACT Guoliang Zhang [zhangguoliang1003@163.com](zhangguoliang1003@163.com) Anhui Hospital of shuguan

FAQs

Why are HBV and HCV important in virus-related hepatocellular carcinoma immunotherapy?

Chronic HBV/HCV infection not only initiates carcinogenesis but also reshapes the hepatic immune microenvironment, which strongly influences immunotherapy efficacy and safety.

Which immunotherapy class is highlighted as a key advance for advanced HCC?

Immune checkpoint inhibitors (ICIs), particularly agents targeting PD-1/PD-L1, are presented as a major breakthrough with clinical benefit.

What strategies are proposed to improve future outcomes for virus-related HCC?

The review emphasizes next-generation immune checkpoints, bispecific antibodies, cellular therapies (e.g., CAR-T, TCR-T, TILs), tumor vaccines, and biomarker-guided personalized treatment using multi-omics and clinical data to optimize sequencing and patient selection.

Sep 30, 2026

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