Macrophage anti-tumor efficacy requires coordinated inflammatory activation and phagocytic function, whether a tumor-intrinsic metabolic regulator simultaneously determines both macrophage anti-tumor mechanisms remains unclear. Here, we screened and identified that farnesyl-diphosphate farnesyltransferase 1 (FDFT1) drives the dual inhibition of macrophage activation and phagocytic function and promotes tumor progression. Mechanistically, tumor-intrinsic FDFT1 directly binds to STAT3 and facilitates the later phosphorylation, which induces PD-L1-dependent suppression of macrophage phagocytosis. Concurrently, FDFT1 binds to and stabilizes cholesterol 25-hydroxylase (CH25H) to promote the secretion of 25-hydroxycholesterol (25HC), suppressing proinflammatory activation of macrophages. Furthermore, FDFT1-mediated dual anti-tumor pathways were validated in mouse tumor models and correlated with clinical pathophysiology. Notably, a small-molecule drug FDFT1-I (2123) targeting FDFT1 inhibits both STAT3-PD-L1 and CH25H/25HC pathways and improves anti-tumor immunity. Collectively, our findings highlight FDFT1 as a tumor-intrinsic metabolic factor promoting tumor development via dual macrophage-dependent mechanisms, suggesting FDFT1 as a promising target for tumor therapy.
Shi et al. (Wed,) studied this question.