Metabolic dysfunction and GZMK+ CD8+ T-cell remodeling in hepatocellular carcinoma: an evidence-stratified, hypothesis-generating review

Abstract

Type 2 diabetes mellitus and metabolic dysfunction associated steatotic liver disease contribute to the growing burden of hepatocellular carcinoma, yet their effects on hepatic antitumor immunity remain incompletely defined. Recent single-cell and spatial profiling studies indicate that hepatocellular carcinoma contains diverse CD8+ T cell states, including cytotoxic, exhausted, tissue-resident, progenitor-like, and transitional phenotypes. This review synthesizes evidence linking hyperglycemia, insulin resistance, lipotoxic injury, chronic inflammation, fibrosis, altered antigen presentation, stromal remodeling, chemokine signaling, and nutrient availability to CD8+ T-cell remodeling in HCC arising in the context of metabolic dysfunction. Particular attention is given to GZMK+ CD8+ T cells, which may reflect non-terminal differentiation, inflammatory adaptation, or transitional immune states rather than conventional cytotoxic effector function. Although GZMK-high CD8+ T cell populations have been reported in hepatocellular carcinoma and therapy-associated immune contexts, direct evidence that type 2 diabetes induces these cells in the liver remains limited. This review specifically examines GZMK+ CD8+ T-cell states within the immunometabolic context of HCC, distinguishes direct hepatic and tumor evidence from extrapolated findings in metabolic liver disease and other inflammatory conditions, and proposes a testable framework for phenotypic, spatial, and functional validation. Integrated single-cell, spatial, protein level, T cell receptor clonality, functional, and clinical studies are needed to define their biological significance and translational value.