The role of glycolysis and lactate in the induction of tumor-associated macrophages immunosuppressive phenotype

Abstract

Growing evidence highlights that glycolysis and tumor-derived lactate could skew tumor-associated macrophages (TAMs) toward an immunosuppressive phenotype. However, the updated research has not been systematically summarized yet. TAMs are educated by the tumor microenvironment (TME) and exert immunosuppressive functions and tumorigenic effects via multiple biological processes. It is well known that lactate generated by aerobic glycolysis is significantly accumulated in TME and promotes tumor progression in solid tumors. Moreover, some recent research demonstrated that glycolysis is activated in TAMs to support M2-like polarization, which is absolutely in contrast with the metabolic profile of M2 macrophages in inflammation. Notably, lactate produced by high levels of glycolysis is not only a metabolic by-product but also an oncometabolite. TAMs could access the biological information delivered by lactate and further enhance protumor functions such as immunosuppression and angiogenesis. Here, we outline the connection between glycolysis and TAM phenotype to elucidate the metabolic characteristics of TAMs. Further, insights into the specific molecular mechanisms of lactate-induced TAM polarization and potential therapeutic targets are summarized. We sought to discuss the reciprocal interaction between tumor cells and TAMs mediated by lactate, which will lay a foundation for the research aiming to elucidate the complex functions of TAMs.

Keywords: G Protein-Coupled Receptor; Glycolysis; Lactate; Monocarboxylate Transporter; Tumor Microenvironment; Tumor-associated Macrophage.