Survival benefits of different immunotherapies for hepatocellular carcinoma: a meta-analysis highlighting age, gender, etiology, and tumor burden.

Background: The heterogeneous efficacy of immunotherapy in hepatocellular carcinoma (HCC) remains unclear. We evaluated efficacy and safety of various immunotherapeutic regimens-including immune checkpoint inhibitor (ICI) monotherapy, dual ICIs, and ICI plus targeted therapy-for unresectable HCC, to identify patient subgroups that benefit most. Methods: Randomized clinical trial evaluating immunotherapy as first-line treatment for unresectable HCC versus tyrosine kinase inhibitors (TKIs) were systematically searched. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios (ORs) for objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) were calculated. Results: Twelve trials were included. Immunotherapy significantly improved OS (HR = 0.77 [0.71-0.83]) and PFS (HR = 0.73 [0.63-0.84]) versus TKIs. ICI plus targeted therapy showed the greatest benefit, reducing mortality by 27% and progression risk by 37%. Subgroup analyses revealed patients aged ≥65 years and male patients derived substantial OS and PFS benefits, particularly from ICI plus targeted therapy, whereas younger patients (<65 years) benefited more from dual ICIs. Additional favorable subgroups included Asian patients, HBV-positive patients, those with poor performance status, macrovascular invasion and/or extrahepatic spread, and Barcelona Clinic Liver Cancer stage C. Notably, female patients showed no significant OS improvement across any regimen. Moreover, non-Asian patients, those with hepatitis C, BCLC stage B, or AFP <400 ng/mL derived limited immunotherapy benefit across regimens. Conclusions: Immunotherapy improves survival in unresectable HCC, with differential subgroup benefits highlighting the necessity for personalized strategies. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42025635108.