Mechanisms of Immune Checkpoint Inhibitor Resistance in Hepatocellular Carcinoma and Strategies for Reversal

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment paradigm for hepatocellular carcinoma (HCC), establishing them as the cornerstone of systemic therapy for advanced stages of the disease. Nonetheless, the response rate remains limited, with only 15% to 20% of HCC patients benefiting from ICIs. Approximately 70% to 80% of cases exhibit resistance to anti-PD1 therapy. Therefore, exploring the biomarkers that can be used to identify the response of patients with HCC to immunotherapy and elucidating the potential mechanisms of immunotherapy resistance contribute to the development of predictive biomarkers and are significant for overcoming resistance and enhancing treatment efficacy. This review synthesizes the current understanding of both primary and acquired resistance mechanisms to ICIs in HCC. Compared with existing reviews, this article uniquely integrates the latest evidence on metabolic reprogramming and tumor immune microenvironment (TIME) remodeling in HCC. It also emphasizes the mechanistic crosstalk between oncogenic signaling, immunosuppression, and metabolic adaptation, providing an updated and more comprehensive framework for understanding ICI resistance. It provides a valuable reference for future research aimed at overcoming therapeutic resistance in this malignancy.