Metabolic reprogramming in the immunosuppression of tumor-associated macrophages.

Abstract

Tumor-associated macrophages (TAMs) are an essential proportion of tumor-infiltrating immune cells in the tumor microenvironment (TME) and have immunosuppressive functions. The high plasticity and corresponding phenotypic transformation of TAMs facilitate oncogenesis and progression, and suppress antineoplastic responses. Due to the uncontrolled proliferation of tumor cells, metabolism homeostasis is regulated, leading to a series of alterations in the metabolite profiles in the TME, which have a commensurate influence on immune cells. Metabolic reprogramming of the TME has a profound impact on the polarization and function of TAMs, and can alter their metabolic profiles. TAMs undergo a series of metabolic reprogramming processes, involving glucose, lipid, and amino acid metabolism, and other metabolic pathways, which terminally promote the development of the immunosuppressive phenotype. TAMs express a pro-tumor phenotype by increasing glycolysis, fatty acid oxidation, cholesterol efflux, and arginine, tryptophan, glutamate, and glutamine metabolism. Previous studies on the metabolism of TAMs demonstrated that metabolic reprogramming has intimate crosstalk with anti-tumor or pro-tumor phenotypes and is crucial for the function of TAMs themselves. Targeting metabolism-related pathways is emerging as a promising therapeutic modality because of the massive metabolic remodeling that occurs in malignant cells and TAMs. Evidence reveals that the efficacy of immune checkpoint inhibitors is improved when combined with therapeutic strategies targeting metabolism-related pathways. In-depth research on metabolic reprogramming and potential therapeutic targets provides more options for anti-tumor treatment and creates new directions for the development of new immunotherapy methods. In this review, we elucidate the metabolic reprogramming of TAMs and explore how they sustain immunosuppressive phenotypes to provide a perspective for potential metabolic therapies.