SCAP-Driven Cholesterol Reprogramming in TAMs Promotes Colorectal Cancer via TFF2-CXCR4 Signaling

Cholesterol metabolism in tumor-associated macrophages (TAMs) and its significance in colorectal cancer (CRC) pathogenesis remain incompletely defined.Here,we demonstrate stage-dependent accumulation of cholesterol and its master regulator SREBP cleavage-activating protein (SCAP) within TAMs in CRC patients,correlating with enhanced tumor proliferation.Mechanistically,the tumor secretome and cholesterol transferred from tumor cells induce the SCAP-mediated cholesterol biosynthesis and uptake pathway in TAMs.Macrophage-specific SCAP ablation suppresses CRC progression.This SCAP-dependent metabolic reprogramming drives TAM differentiation into Macrophage Receptor with Collagenous Structure (MARCO)+ macrophages.Targeted depletion of MARCO+ macrophages similarly inhibits tumorigenesis,attributable to MARCO+ macrophage-derived secretion of Trefoil Factor 2 (TFF2),which binds C X C motif chemokine receptor 4 (CXCR4) on CRC cells,activating MEK/ERK and PI3K/AKT signaling to accelerate proliferation.Our findings establish TAM cholesterol enrichment as functionally coupled to their differentiation,with SCAP as a central regulator and the TFF2-CXCR4 signaling axis as a promising therapeutic vulnerability in CRC.