Oncolytic Virus-Based Immunotherapy for Hepatocellular Carcinoma: Strategies for Enhanced Efficacy and Clinical Application.

Abstract

Hepatocellular carcinoma (HCC) is a top cause of global cancer mortality, with fibrotic stroma, impaired perfusion and severe immunosuppressive tumor microenvironment (TME) leading to poor responses to conventional therapies. Oncolytic viruses (OVs) are emerging investigational immunotherapeutic agents, which exert dual effects of direct tumor lysis and TME remodeling to restore anti-tumor immunity. This review aims to systematically summarize preclinical and clinical advances of OV therapy for HCC, analyze existing bottlenecks and propose targeted optimization strategies. We establish three novel exclusive analytical frameworks tailored to cirrhotic HCC, and confirm that engineered OVs exert potent anti-tumor and immunomodulatory effects with promising preliminary efficacy and acceptable safety in refractory HCC based on early-phase small-cohort studies. Key challenges including inefficient tumor targeting and limited delivery are prominent in cirrhotic patients, and we summarize multiple synergistic strategies to address these issues. Our findings, integrated discussion and conclusions fill the research gap of cirrhosis-oriented OV translational research for HCC; this work provides standardized evaluation criteria and a unified translational roadmap, delivering novel scientific insights and practical guidance for tumor immunotherapy research within the journal's scope. Collectively, engineered OVs show potential for future clinical application in advanced HCC, while large-scale controlled clinical evidence is still urgently needed.