Immune Checkpoint Inhibitors in Hepatocellular Carcinoma: Mechanisms of Action, Therapeutic Efficacy, and Emerging Combination Strategies

Over the past decade, immune checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC) at the systemic level. This review analyzes 210 studies (20152024) to trace the progression from initial PD-1 blockade trials to modern multi-agent protocols, emphasizing the transformation of HCCs immune-excluded milieu into one that fosters sustained antitumor activity. Mechanistically, pathways involving PD-1/PD-L1, CTLA-4, LAG-3, and TIM-3 induce T-cell dysfunction, hinder neoantigen recognition, and attract immunosuppressive macrophages. ICIs counteract these effects, revitalizing cytotoxic T-cell migration and diversifying T-cell receptor profiles. Pooled data from phase II/III trials indicate monotherapy response rates of 1430%, increasing to 2746% with combinations such as atezolizumab/bevacizumab or durvalumab/tremelimumab. However, these regimens are accompanied by higher-grade adverse events (2537%). Challenges such as inconsistent biomarker expression, loss of interferon- signaling-induced resistance, and overlapping toxicities persist. To address these, the author suggests: (1) multi-parameter biomarker models combining PD-L1, TMB, and circulating CD8+ Ki-67 levels; (2) staggered dosing to separate ICI initiation from anti-angiogenic therapy; and (3) pharmacovigilance systems to track delayed toxicities and tailor treatment withdrawal.