Hepatocellular carcinoma (HCC), accounting for over 90% of primary liver cancers, remains a major global challenge for healthcare professionals. While immunotherapy has transformed the landscape of cancer treatment, its success is often limited by immune resistance, particularly through T cell exhaustion which remains a major barrier to effective immune responses in solid tumours, including HCC. As tumours progress, T cells undergo a gradual loss of functionality due to continuous antigen exposure and fail to exert effective anti-tumour responses. During this process, alterations in the epigenome, transcriptome, signalling pathways, and tumour metabolome, in addition to interactions with other cells in the tumour microenvironment, efficiently contribute to T cell exhaustion. Restoring T cell function brings hope for improving therapy outcomes and providing new treatment modalities for HCC patients. In this review, we explore the key cellular and molecular mechanisms driving T cell exhaustion, including the roles of immunosuppressive cells, metabolic stress, and epigenetic alterations focusing on HCC. We also discuss current and emerging strategies aimed at preventing or reversing T cell exhaustion, such as epigenetic modulation, immune checkpoint blockade, metabolic reprogramming, and combination therapies. Understanding these interconnected pathways is critical for designing more effective immunotherapy-based approaches for liver cancer.
Keywords: T cell exhaustion; epigenetic modifications; hepatocellular carcinoma; signalling pathways; solid tumour immunotherapy; tumour metabolomics.
© 2026 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.