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Breast cancer–associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells

Macrophage-secreted TGF-β promotes glycolysis in tumor cells to support angiogenesis and immunosuppression. TAMs reprogram tumor metabolism Macrophages in the tumor microenvironment [called tumor-associated macrophages (TAMs)] often support tumor growth and metastatic progression. Using a mix of in vivo and coculture work with primary macrophages, Gomez et al. found that secretion of the cytokine TGF-β from anti-inflammatory TAMs suppressed the abundance of succinate dehydrogenase in breast cancer cells. The loss of this metabolic enzyme promoted glycolysis, thereby enhancing tumor growth, angiogenesis, and immunosuppression. Depleting anti-inflammatory TAMs or blocking TGF-β suppressed these effects in vivo. The findings reveal a metabolic mechanism underlying the protumorigenic roles of TAMs. Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with breast cancer cells in culture and in mice. We found that anti-inflammatory TAMs promoted a metabolic state in breast cancer cells that supported various protumorigenic phenotypes. Anti-inflammatory TAMs secreted the cytokine TGF-β that, upon engagement of its receptors in breast cancer cells, suppressed the abundance of the transcription factor STAT1 and, consequently, decreased that of the metabolic enzyme succinate dehydrogenase (SDH) in the tumor cells. The decrease in SDH levels in tumor cells resulted in an accumulation of succinate, which enhanced the stability of the transcription factor HIF1α and reprogrammed cell metabolism to a glycolytic state. TAM depletion-repletion experiments in a 4T1 mouse model additionally revealed that anti-inflammatory macrophages promoted HIF-associated vascularization and expression of the immunosuppressive protein PD-L1 in tumors. The findings suggest that anti-inflammatory TAMs promote tumor-associated angiogenesis and immunosuppression by altering metabolism in breast cancer cells.