Lactic acid promotes macrophage polarization through MCT-HIF1α signaling in gastric cancer

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 HIF1 alpha knockdown, significantly abrogated CD163 and ARG1 expression in THP-1 cells, suggesting that MCT-HIF1 alpha signaling is responsible for macrophage polarization. Collectively, our findings identify the lactate-MCT-HIF1 alpha axis as a critical signaling cascade that couples metabolic reprogramming to macrophage polarization in gastric cancer.