Reprogramming of energy metabolism and evading immune are two emerging hallmarks of cancers. Accumulating evidence suggest that reprogrammed energy metabolism contributes to a tumor-suppressive immune microenvironment in cancers. Macrophages are the most abundant immune cells in the tumor microenvironment and M2 macrophages are profoundly implicated in tumor initiation and progression. By gene set enrichment analysis, we found that glycolysis signature was closely associated with the M2 macrophage phenotype in gastric cancer. Enhanced glycolysis is characterized by significant production of lactate. Interestingly, we found that lactic acid is able to skew macrophage toward a M2-like state. Treatment of THP-1 cells or human monocytes with gastric cancer cell-derived conditioned media or lactic acid significantly increased expression of M2-related markers and faintly attenuated expression of M1-related markers. Moreover, knockdown of LDHA suppressed the ability of gastric cancer to skew macrophage toward M2 phenotype as revealed by reduced expression of M2-related markers and cytokines. Mechanistically, a-cyano-4-hydroxycinnamate (CHC), a monocarboxylate channel transporter (MCT) inhibitor, or HIF1α knockdown, significantly abrogated CD163 and ARG1 expression in THP-1 cells, suggesting that MCT-HIF1α signaling is responsible for macrophage polarization. Collectively, our findings identify the lactate-MCT-HIF1α axis as a critical signaling cascade that couples metabolic reprogramming to macrophage polarization in gastric cancer.

中文翻译：

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乳酸通过MCT-HIF1α信号传导促进胃癌巨噬细胞极化。

重新编程能量代谢和逃避免疫是癌症的两个新兴标志。越来越多的证据表明，重新编程的能量代谢有助于癌症抑制肿瘤的免疫微环境。巨噬细胞是肿瘤微环境中最丰富的免疫细胞，M2巨噬细胞与肿瘤的发生和发展密切相关。通过基因集富集分析，我们发现糖酵解信号与胃癌的M2巨噬细胞表型密切相关。增强的糖酵解的特征在于大量产生乳酸。有趣的是，我们发现乳酸能够使巨噬细胞偏向M2样状态。用胃癌细胞衍生的条件培养基或乳酸处理THP-1细胞或人单核细胞可显着增加M2相关标志物的表达，并减弱M1相关标志物的表达。而且，通过降低M2相关标志物和细胞因子的表达可以看出，敲除LDHA抑制了胃癌使巨噬细胞向M2表型倾斜的能力。从机理上讲，α-氰基-4-羟基肉桂酸酯（CHC），一种单羧酸盐通道转运蛋白（MCT）抑制剂或HIF1α敲低可显着废除THP-1细胞中CD163和ARG1的表达，提示MCT-HIF1α信号是巨噬细胞极化的原因。总的来说，我们的发现将乳酸-MCT-HIF1α轴确定为关键信号传导级联，将代谢重编程与胃癌中的巨噬细胞极化耦合在一起。