PD-1+/CXCR6+CD8+T lymphocytes promote MASLD malignant progression through inflammatory and immune dysregulation

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to hepatocellular carcinoma (HCC), but the role of CD8 + T cells from MASLD to HCC progression is unclear. This study investigates the dynamic changes in CD8 + T cells via MASLD malignancy to analyzing underlying mechanisms using animal models and clinical validation. MASLD model mice were fed with a high-fat diet (HFD) or HFD plus 2-fluorene-acetylamino (HFD/HCC). Model livers exhibited lipid accumulation with high triglyceride, cholesterol and low-density lipoprotein, and hepatocyte damages (ALT & AST, P < 0.001). During MASLD progression, the alterations of CD8 + T, PD-1 + CD8 + T and CXCR6 + CD8 + T cells analyzed by flow cytometry showed intrahepatic CD8 + T cell ratio decreased while PD-1 + and CXCR6 + subsets significantly increased ( P < 0.05) in the HFD/HCC group. Hepatic cells by single-cell sequencing revealed CD8 + T cells interacting with Kupffer/neutrophil cells and contributing to inflammation and immune dysfunction. Clinical samples from MASLD/HCC patients confirmed the higher ratios of CD8 + T, PD-1 + CD8 + T, and CXCR6 + CD8 + T cells in HCC patients with MASLD, accompanied by lipid metabolism abnormalities and hepatocyte injury. These findings demonstrated that decreased CD8 + T cells, particularly increased PD-1 + /CXCR6 + subsets, could drive MASLD malignancy via inflammatory and immune dysregulation, highlighting potential targets for MASLD immunotherapy. • MASLD malignancy model exhibited the dynamic alterations of hepatic immune cells in lipid-rich microenvironment, characterized by a decrease in proportion of CD8 + T cells, while PD-1 + and CXCR6 + subsets significantly increased, which was validated by clinical evidence. • Mechanistically, interactions between CD8 + T cells and Kupffer cells/neutrophils, particularly increased PD-1 + /CXCR6 + subsets, could drive hepatocyte malignancy via inflammatory and immune dysregulation, highlighting potential targets for MASLD immunotherapy.