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.

肿瘤相关巨噬细胞（TAM）可以以促炎和抗炎状态存在。抗炎 TAM（也称为 M2 极化）通常会抑制抗肿瘤免疫反应并增强癌症的转移进展。为了探索这种现象背后的机制，我们从小鼠和人类中分离出巨噬细胞，将它们离体极化，并在培养物和小鼠体内检查它们与乳腺癌细胞的功能相互作用。我们发现抗炎 TAM 促进乳腺癌细胞的代谢状态，支持各种促肿瘤表型。抗炎 TAM 分泌细胞因子 TGF-β，该细胞因子与乳腺癌细胞中的受体结合后，抑制转录因子 STAT1 的丰度，从而降低肿瘤细胞中代谢酶琥珀酸脱氢酶 (SDH) 的丰度。肿瘤细胞中 SDH 水平的降低导致琥珀酸的积累，从而增强了转录因子 HIF1α 的稳定性，并将细胞代谢重新编程为糖酵解状态。 4T1 小鼠模型中的 TAM 耗尽-补充实验还表明，抗炎巨噬细胞促进肿瘤中 HIF 相关的血管化和免疫抑制蛋白 PD-L1 的表达。研究结果表明，抗炎 TAM 通过改变乳腺癌细胞的代谢来促进肿瘤相关的血管生成和免疫抑制。