Immunotherapy in hepatocellular carcinoma: translating mechanistic insights into clinical advances

Hepatocellular carcinoma is the most common primary liver cancer and a leading cause of cancer-related mortality worldwide. Traditional systemic therapies, such as tyrosine kinase inhibitors, offer limited survival benefits, prompting the emergence of immunotherapy as a transformative approach. This review synthesizes mechanistic insights into the tumor microenvironment of hepatocellular carcinoma with clinical evidence from pivotal trials on immune checkpoint inhibitors. It summarizes outcomes from monotherapy and combination regimens incorporating antiangiogenic agents, tyrosine kinase inhibitors, radiotherapy, and locoregional therapies like transarterial chemoembolization or hepatic arterial infusion chemotherapy. Emerging modalities, including therapeutic vaccines, oncolytic viruses, Toll-like receptor agonists, and adoptive cell therapies, are also examined. Immune checkpoint inhibitors targeting programmed cell death protein 1, its ligand, and cytotoxic T-lymphocyte-associated protein 4 elicit durable responses in subsets of patients, though monotherapy provides modest overall benefits. Combination strategies, such as atezolizumab plus bevacizumab, tremelimumab–durvalumab (STRIDE), and nivolumab plus ipilimumab (CheckMate-9DW), have set new standards of care by significantly extending overall survival with acceptable toxicity. Resistance mechanisms involve tumor-intrinsic factors like beta-catenin signaling and antigen presentation defects, alongside microenvironmental elements including regulatory T cells, myeloid-derived suppressor cells, and cytokine networks. Effective management of immune-related adverse events, particularly hepatic toxicities, is critical. Immunotherapy has revolutionized hepatocellular carcinoma treatment, fostering multimodal and personalized strategies. Future directions emphasize validated biomarkers, optimized sequencing, and randomized trials to broaden long-term survival gains.