APOE-mediated immunometabolic reprogramming of macrophages drives lipid delivery to tumor cells in clear-cell renal cell carcinoma — a metabolic checkpoint

Extensive evidence highlights the critical role of the von Hippel-Lindau (VHL) tumor suppressor gene in the initiation and progression of ccRCC. Our previous studies demonstrated that VHL deficiency in renal tubular epithelial cells promotes activation of the endothelial vascular network and facilitates immune cell infiltration, particularly by macrophages (Ms), into the ccRCC microenvironment.

These interactions between VHL-deficient renal cells and the recruited stromal components are essential for ccRCC development. In our investigation of ccRCC-associated macrophages, we observed a significant upregulation of genes related to lipid metabolism in MΦs co-cultured with VHL-deficient tubular cells. Further analysis confirmed that these tumor-associated macrophages (TAMs) actively uptake lipids, and we called them lipid-laden macrophages (LLMs).