Chaperone-mediated autophagy is a tumor-suppressive mechanism in hepatocellular carcinoma.

Chaperone-mediated autophagy (CMA) is a selective lysosomal pathway essential for proteostasis and stress adaptation that declines with aging and metabolic disease, conditions closely linked to hepatocellular carcinoma (HCC). Using genetically engineered mouse models with systemic, hepatocyte-specific, or T cell-specific deletion of the CMA regulator LAMP2A in an MYC-driven, TP53-deficient HCC context, we demonstrate that CMA exerts cell-type-dependent tumor-suppressive functions. Hepatocyte-intrinsic CMA loss promotes early malignant transformation, whereas T cell-specific CMA deficiency impairs early immune-mediated tumor control but is also required to sustain tumor growth. Proteomic profiling identifies the cohesin complex component STAG2 as a putative CMA substrate that accumulates in CMA-dysregulated hepatocytes, a finding validated in human HCC tissues, shown to drive cell cycle dysregulation and proliferation, contributing to hepatocarcinogenesis. These results establish CMA as a dual hepatocyte- and immune-dependent mechanism that suppresses liver tumorigenesis and positions STAG2 as a CMA-controlled node with therapeutic relevance in HCC.