Unraveling the connection: M2 macrophage polarization and cancer metabolism

Abstract

Cancer remains one of the leading causes of morbidity and mortality globally, driven by genetic alterations, uncontrolled cell proliferation, and metabolic reprogramming. The tumor microenvironment (TME) is a highly dynamic and heterogeneous system composed of tumor cells, immune cells, stromal cells, and extracellular matrix (ECM) components, which influence cancer progression. Tumor-associated macrophages (TAMs), especially those polarized into the M2 phenotype, play a critical role in modulating this environment. M2 macrophages promote tumor progression through mechanisms such as immune suppression, angiogenesis, and metastasis. This polarization is heavily influenced by the altered metabolic landscape of tumors, where the Warburg effect leads to excessive lactate production, which in turn drives M2 polarization through G protein-coupled receptor 132 (GPR132). M2 macrophages secrete cytokines like IL-10, transforming growth factor β (TGF-β), and vascular endothelial growth factor (VEGF), which contribute to immune escape, tumor growth, and metastasis. The metabolic shifts within TAMs, especially the transition from oxidative phosphorylation to glycolysis, further support the pro-tumoral functions of these cells. This review explores the intricate relationship between M2 macrophage polarization bias, tumor metabolism, and the resulting impact on cancer progression, highlighting the potential of targeting these pathways for therapeutic strategies. The findings suggest that M2 macrophage polarization could serve as a key prognostic factor for cancer outcomes and provide a basis for future research into therapeutic interventions that target macrophage polarization and the tumor metabolic milieu.

Keywords

Cancer / M2 macrophages / metabolism / Warburg effect

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