Efficacy and safety of immune checkpoint inhibitors in hepatocellular carcinoma: a comprehensive umbrella review of meta-analyses

Objective: To summarize and assess the existing evidence on the effectiveness and safety of immune checkpoint inhibitors (ICIs) treatments in patients diagnosed with hepatocellular carcinoma (HCC). Design: An umbrella review encompassing current meta-analyses reporting clinical effectiveness or safety outcomes of ICIs. Data sources: PubMed, Web of Science, Embase, the Cochrane Systematic Reviews Database, and reviewed reference sections of relevant research articles. Study selection: We included all systematic reviews with meta-analyses of observational or interventional studies evaluating ICIs in patients with HCC. The patient cohorts comprised adults with HCC, including both those with advanced disease and those receiving neoadjuvant therapy for resectable tumors. Results: Fifty-four meta-analyses (covering 166 direct comparisons and over 35,000 patients) were included. High-quality evidence demonstrated that ICI plus tyrosine kinase inhibitor (TKI) significantly improved overall survival (HR 0.58, 95% CI 0.49–0.70) and progression-free survival (HR 0.58, 95% CI 0.51–0.67), and increased objective response rates (OR 3.17, 95% CI 2.21–4.54), compared with TKI monotherapy. Triple combination therapy (ICI + TKI + locoregional therapy) yielded the largest absolute gains in survival (HR 0.48, 95% CI 0.36–0.64) and tumor response, but evidence was of moderate-quality due to protocol heterogeneity. Subgroup analyses indicated greater benefit in hepatitis B-related HCC and male patients. ICIs demonstrated a manageable safety profile, with increased risks of hypertension and thyroid dysfunction, but no significant excess in most grade ≥3 toxicities. Only 11.1% of meta-analyses were of high methodological quality; just 24.4% of statistically significant outcomes were graded as high-quality, and all evidence was class IV by sample size. Conclusion: ICI-based regimens, particularly ICI + TKI doublets, offer substantial survival and tumor response benefits for HCC with manageable toxicity. Triple and conversion strategies are promising but require further high-quality randomized trials. Current recommendations are limited by the generally low quality and size of existing meta-analyses, underscoring the need for rigorous primary studies and robust future evidence syntheses.