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.