Deficient chaperone-mediated autophagy in macrophages aggravates colitis and colitis-associated tumorigenesis in mice

作者：Weichun Zhu, Zehao Chen, Yun‐Qian Gao, Chungang Zhai, Xia Li, Ning Wang, Kang Fu, Wentao Chen, Wentao Chen, Jieqiong Peng, Dan Xu, Lei Qiao, Wenqiang Chen, Wenqiang Chen · 发表于：Molecules and Cells · 年份：2025 · DOI：10.1016/j.mocell.2025.100298 · 被引用次数：3 · 研究领域：Autophagy in Disease and Therapy、Endoplasmic Reticulum Stress and Disease、Cancer, Hypoxia, and Metabolism

Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy responsible for the degradation of specific cytosolic proteins within lysosomes. Recent research has established a significant correlation between CMA and colorectal cancer (CRC). However, the majority of current research focuses on tumor parenchymal cells, with limited attention paid to the expression and role of CMA in tumor stromal cells, particularly in tumor-associated macrophages (TAMs). In this study, we generated myeloid-specific LAMP2A-knockout and knock-in mice to investigate the role of macrophage CMA in dextran sodium sulfate (DSS)-induced colitis and azoxymethane/dextran sodium sulfate-induced CRC. Our findings indicated that the expression of LAMP2A, the rate-limiting component of CMA, was reduced in tumor-associated macrophages of both human and mouse CRC tissues. The knockout of LAMP2A in macrophages exacerbated experimentally induced colitis and colitis-related CRC, whereas its overexpression in macrophages alleviated the progression of colitis and CRC in mice. Notably, we observed increased angiogenesis within the tumor mass of CRC tissues from LAMP2A-mØKO mice. Mechanistically, LAMP2A deficiency elevated the protein levels of HIF-1α, thereby enhancing the secretion of its target genes, vascular endothelial growth factor A and IL-1β, which are 2 important proangiogenic cytokines. Our study suggests that the activation of CMA in macrophages may represent a promising therapeutic strateg...