Macrophage-Supported Metabolic Adaptation Drives Tumor Survival under Nutrient Stress

Triple-negative breast cancer (TNBC) is a prevalent cancer characterized by pervasive hypoxia, abundant cell death, and pervasive infiltration of macrophages. Here, we report that similar types of breast cancer exhibit distinct metabolic environments that inform tumor-associated macrophage efferocytosis, tumor progression, and treatment efficacy. We show that mouse and human macrophages exposed to prolonged hypoxia release metabolites that rescue growth of selective TNBC lines when glutamine is absent or glutamine metabolism is inhibited in vitro. We found that hypoxia-conditioned macrophages decrease consumption of glutamine and increase consumption of arginine as well as increase release of the arginine metabolism intermediate ornithine.Additionally, provision of exogenous ornithine, but not arginine, significantly rescued growth of TNBC lines sensitive to rescue by macrophage-released metabolites. Mechanistically, TNBC shunted ornithine into the proline synthesis pathway to support aerobic glycolysis and oxidative pentose phosphate pathway activity. Finally, we found that depletion of tumor-associated myeloid cells resulted in decreased growth and concomitant loss of proline synthesis in glutaminase inhibition-resistant TNBC in vivo. Thus, macrophages alter their metabolic state in response to prolonged hypoxia to support growth of TNBC in limited nutrient environments.