Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis

Hypoxic tumor-associated macrophages (TAMs) acquire angiogenic and immunosuppressive properties. Yet it remains unknown if metabolic changes influence these functions. Here, we argue that hypoxic TAMs strongly upregulate the expression of REDD1, a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis in TAMs and curtails their excessive angiogenic response, with consequent formation of abnormal blood vessels. Accordingly, REDD1 deficiency in TAMs leads to the formation of smoothly aligned, pericyte-covered, functional vessels, which prevents vessel leakiness, hypoxia, and metastases. Mechanistically, highly glycolytic REDD1-deficient TAMs outcompete endothelial cells for glucose usage that thwarts vascular hyperactivation and promotes the formation of quiescent vascular junctions. Tuning down glycolysis in REDD1 knockout TAMs re-establishes abnormal angiogenesis and metastases. On this basis, we prove that the anti-tumor effect of mTOR inhibitors is partly countered by the deleterious outcome of these drugs on TAMs. Our data provide a functional link between TAM metabolism and tumor angiogenesis. [Display omitted] •REDD1 deletion enhances glucose uptake and glycolysis in hypoxic TAMs via mTOR•Enhanced glycolysis in REDD1 KO TAMs leads to glucose competition (GC) with tECs•GC by REDD1 KO TAMs stabilizes tumor EC junctions and vessels preventing metastasis•mTOR activation is antitumoral in hypoxic TAMs but protumoral in cancer cells Wenes et al. show that enhancing glycolysis via mTOR activation in hypoxic tumor-associated macrophages (TAMs) reduces endothelial glucose availability and promotes the formation of an organized tumor vasculature, which helps to restore oxygenation and prevent metastasis. The anti-tumor effects of mTOR inhibitors are mitigated by their effects on TAM metabolism.