Hepatic T-cell dysfunction in chronic liver disease and hepatocellular carcinoma: a spatial systems immunology framework for precision immunotherapy

BACKGROUND: Chronic liver diseases, including chronic viral hepatitis, metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma (HCC), are characterized by progressive immune dysregulation that drives chronic inflammation, fibrosis, and hepatocarcinogenesis. Although hepatic T-cell dysfunction is a hallmark of these diseases, it is still predominantly investigated through isolated molecular pathways rather than as an integrated property of the hepatic immune ecosystem. This reductionist perspective has limited mechanistic understanding and the development of durable immunotherapeutic strategies. AREAS COVERED: This review proposes a spatial systems-immunology framework as its central conceptual contribution. The framework explains hepatic T-cell dysfunction as an emergent systems-level state arising from coordinated interactions among immune, metabolic, stromal, vascular, and spatial regulatory programs. The translational implications of this framework for biomarker-guided precision immunotherapy in chronic liver disease and HCC are further discussed. EXPERT OPINION: Future advances in liver immunotherapy should prioritize mechanism-based combination therapies guided by multidimensional immune, metabolic, stromal, and spatial biomarkers rather than continued optimization of individual molecular targets. In this review, it is argued that the proposed spatial systems-immunology framework provides a practical foundation for this transition and may improve patient stratification, therapeutic durability, and long-term clinical outcomes in chronic liver disease and HCC.