PD-1/CXCR6CD8T lymphocytes promote MASLD malignant progression through inflammatory and immune dysregulation.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely linked to hepatocellular carcinoma (HCC), but the role of CD8T cells from MASLD to HCC progression is unclear. This study investigates the dynamic changes in CD8T 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&#xa0;<&#xa0;0.001). During MASLD progression, the alterations of CD8T, PD-1CD8T and CXCR6CD8T cells analyzed by flow cytometry showed intrahepatic CD8T cell ratio decreased while PD-1and CXCR6subsets significantly increased (P&#xa0;<&#xa0;0.05) in the HFD/HCC group. Hepatic cells by single-cell sequencing revealed CD8T cells interacting with Kupffer/neutrophil cells and contributing to inflammation and immune dysfunction. Clinical samples from MASLD/HCC patients confirmed the higher ratios of CD8T, PD-1CD8T, and CXCR6CD8T cells in HCC patients with MASLD, accompanied by lipid metabolism abnormalities and hepatocyte injury. These findings demonstrated that decreased CD8T cells, particularly increased PD-1/CXCR6subsets, could drive MASLD malignancy via inflammatory and immune dysregulation, highlighting potential targets for MASLD immunotherapy.