Differential Efficacy of Immunotherapy for Hepatocellular Carcinoma by Aetiology: A Systematic Review and...

The tumour immune microenvironment (TIME) of hepatocellular carcinoma (HCC) is distinctive across different aetiologies, potentially leading divergent responses to immune checkpoint inhibitors (ICIs). This study compared the efficacy of ICI-based therapies between viral and nonviral HCC.

This review was implemented as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching multiple databases for studies published up to June 2025. Studies reporting overall survival (OS) or progression-free survival (PFS) stratified by HCC aetiology (viral vs nonviral) were included. Pooled hazard ratios (HRs) were computed using random-effects models.

Analysis of 26 studies revealed a hierarchy in survival benefit. In the indirect comparison (ICI vs non-ICI controls), the survival benefit was most significant in hepatitis B virus-HCC (HBV-HCC) (OS HR: 0.67; PFS HR: 0.58), intermediate in hepatitis C virus-HCC (HCV-HCC) (OS HR: 0.84; PFS HR: 0.75), and most attenuated in nonviral HCC (OS HR: 0.88; PFS HR: 0.71). In the direct comparison among patients receiving ICIs, viral HCC was associated with significantly superior PFS (HR: 0.84) and a trend toward improved OS (HR: 0.91) over nonviral HCC. Heterogeneity was observed, partly due to geographic region and treatment-line variations.

Immunotherapy efficacy in HCC demonstrates a clear aetiology-based hierarchy, with the strongest benefit in HBV-HCC, intermediate in HCV-HCC, and most modest in nonviral HCC. Aetiology is a key determinant of treatment response and should be integrated as a stratification factor in clinical practice and trial design.

CRD42025638434.