SYSTEMATIC REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicPersonalized Immuno-Oncology: The Impact of Age and Sex on Anti-Tumor Immune ResponsesView all 3 articles
Survival Benefits of Different Immunotherapies for Hepatocellular Carcinoma: A Meta-Analysis Highlighting Age, Gender, Etiology, and Tumor Burden
Provisionally accepted
- 1First Affiliated Hospital of Soochow University, Suzhou, China
- 2Affiliated Hospital of Jiangnan University, Wuxi, China
- 3Soochow University, Suzhou, China
- 4The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
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
Keywords: Hepatocellular Carcinoma, Immunotherapy, subgroup analysis, age, gender, Meta-analysis, Immune checkpoint inhibitor
Received: 25 Sep 2025; Accepted: 27 Nov 2025.
Copyright: © 2025 Guan, Li, Ding, Sun, Li, Yang, Hong and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mingcheng Guan
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.