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

Clear-cell renal cell carcinoma (ccRCC) is defined by cancer cells with lipid-filled cytoplasm that appears "clear" in tissue preparations; however, the origin of these lipids and their role in tumor progression remain unclear. Notably, cultured ccRCC cells rarely exhibit the clear-cell phenotype in vitro, suggesting that lipid accumulation in ccRCC is not cell-autonomous. Here we show that tumor-associated macrophages (TAMs) undergo immunometabolic reprogramming and serve as major suppliers of lipids for ccRCC cells. Upon activation by the tumor suppressor gene VHL-deficient kidney tubule cells, TAMs acquire adipogenic and cholesterol metabolic signatures, accumulate lipids, and differentiate into lipid-laden macrophages (LLMs) via a TGF-β-APOE-dependent pathway. LLMs then transfer lipids directly to tumor cells through tunneling nanotubes (TNTs). Lipidomic analyses revealed that LLMs and recipient tumor cells share nearly identical lipid profiles enriched in cholesterol and phosphatidates, but not triglycerides. In patient cohorts, elevated APOE expression levels in macrophages (MΦs) correlated with advanced disease stages. In vivo, disruption of MΦ-specific APOE expression abrogated the clear-cell phenotype, reduced tumor growth, and suppressed metastasis in autochthonous and orthotopic xenograft ccRCC models. These findings identify a previously unrecognized MΦ-tumor crosstalk in which reprogrammed TAMs supply lipids to tumor cells, driving the clear-cell phenotype and disease progression. Targeting the TGF-β-APOE axis or TNT-mediated lipid transfer represents a potential therapeutic strategy. More broadly, this work supports a "metabolic checkpoint" paradigm, revealing a therapeutically amenable vulnerability in ccRCC.