Immunology, immunotherapy, and the tumor microenvironment in hepatocellular carcinoma: a comprehensive review

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death globally, characterized by an immunosuppressive tumor microenvironment (TME) that impairs immune surveillance. Immunotherapy has emerged as a transformative option; however, durable responses remain limited. The purpose of this review is to synthesize recent advances in HCC immunology, immunotherapy, and the TME. Literature was identified via PubMed and ClinicalTrials.gov (January 2001-May 2025), focusing on clinical and translational studies. We outline the immunological landscape of HCC, emphasizing the roles of T cells, natural killer cells, macrophages, dendritic cells, myeloid-derived suppressor cells, and regulatory T cells in shaping tumor immunity. TME components include cancer-associated fibroblasts, tumor-associated macrophages, suppressive cytokines, angiogenesis, hypoxia, metabolic reprogramming, and the gut-liver axis. We examine their interactions with immunotherapy, mechanisms of resistance, and combination strategies. Emerging biomarkers - such as tertiary lymphoid structures, PD-L1, tumor mutational burden, gene signatures, and gut microbiota - are reviewed for patient stratification. Immunotherapy has reshaped HCC management, but resistance, biomarker limitations, and heterogeneity remain major challenges. Advances will require TME reprogramming, multi-parametric biomarkers, and personalized strategies. Integration with targeted and locoregional approaches may achieve durable responses and move toward precision immuno-oncology, transforming HCC into a manageable or curable disease.