Abstract Clear-cell renal cell carcinoma (ccRCC) is defined by its lipid-rich cytoplasm, yet the origin of these lipids and their contribution to tumor progression remain unclear. Strikingly, while ccRCC cells seldom exhibit the clear-cell phenotype in vitro, they consistently do so in vivo, indicating the importance of tumor microenvironment. Using in vitro coculture, in vivo mouse models, and human ccRCC samples, we investigated the role of tumor-associated macrophages (TAMs) in lipid transfer to cancer cells. Gene expression profiling, lipidomics, imaging of tunneling nanotubes (TNTs), and functional assays with genetic and pharmacological perturbations were performed to delineate underlying mechanisms. We identified tumor-associated macrophages (TAMs) as principal suppliers of lipids to ccRCC cells. Upon activation by VHL-deficient kidney tubule cells, TAMs acquired adipogenesis and cholesterol metabolism signatures, accumulated lipids, and differentiated into lipid-laden macrophages (LLMs) via a TGF-β-APOE-dependent program. LLMs delivered lipids directly to tumor cells through tunneling nanotubes (TNTs), a process requiring CDC42-mediated actin remodeling. Lipidomic profiling confirmed that LLMs and recipient tumor cells shared nearly identical lipid signatures, which consist mostly of cholesterol and phosphatidates, but not triglycerides. In patient cohorts, infiltration of APOE-enriched macrophages (MFs) correlated with poor survival. In vivo, disruption of APOE expression or TNT formation in MFs abrogated clear-cell morphology, reduced tumor growth, and suppressed metastasis in both autochthonous and orthotopic xenograft models. Our study uncovers a previously unrecognized macrophage-tumor interaction in which TAMs undergo immune-metabolic reprograming. They then deliver lipids to tumor cells, drive the hallmark clear-cell phenotype, and promote ccRCC progression. Targeting the TGF-β–APOE axis or TNT-mediated lipid transfer represents a promising therapeutic strategy for ccRCC. Citation Format: Thi-Ngoc Nguyen, Hieu-Huy Nguyen-Tran, Kuo-How Huang, Guan-Lin Kuo, Shi-Min Liao, Wei-Chou Lin, Tien Hsu. APOE-mediated immune-metabolic reprogramming of macrophages drives lipid delivery to tumor cells in clear-cell renal cell carcinoma abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₂): Abstract nr PR005.
Nguyen et al. (Fri,) studied this question.