Converting ‘cold’ to ‘hot’ hepatocellular carcinoma for improved immunotherapy (Review)

Hepatocellular carcinoma (HCC) often exhibits an immunologically ‘cold’ tumor microenvironment (TME) characterized by poor T cell infiltration and active immunosuppressive mechanisms, limiting the efficacy of immunotherapies such as immune checkpoint inhibitors (ICIs). Therefore, converting immunologically cold HCC tumors into ‘hot’, immune‑reactive tumors has emerged as a critical strategy to enhance immunotherapy responsiveness. In the present review, the tumor immune landscape in HCC is summarized, and the mechanisms underlying its immunologically cold phenotype, and current strategies for reprogramming the TME toward an immune‑active state are described. In addition, the roles of various immune cells, cytokines and tumor‑intrinsic pathways in driving immune exclusion and tolerance are discussed. Therapeutic approaches include ICI‑based combinations with anti‑angiogenic agents or locoregional therapies, as well as dual checkpoint blockade. Other strategies involve targeting immunosuppressive cell populations, oncolytic virus therapy, cancer vaccines, adoptive cell therapies and epigenetic modulators. Clinical evidence supports the potential of these strategies, with several combinations demonstrating improved response rates and survival. Research aims to optimize these therapies, identify predictive biomarkers and explore novel immune targets to further improve outcomes. Overall, converting HCC from an immunologically cold‑to‑hot tumor represents a promising paradigm to potentiate immunotherapy efficacy, although additional studies and innovative strategies are required to achieve durable benefits for a broader population of patients with HCC.