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

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.

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.

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.

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.