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.

Role of LGMN in tumor development and its progression and connection with the tumor microenvironment

“…To control the transcription of their target genes, these oligomeric complexes enter the nucleus ( Conidi et al, 2011 ; Meng et al, 2013 ). To overcome EMT-related drug resistance, was investigated the TGF-3/FAK pathway targeting lipid metabolism and used LGMN activation to accomplish tumor-related macrophage repolarization ( Wang et al, 2022 ).…”

The rising roles of exosomes in the tumor microenvironment reprogramming and cancer immunotherapy

“…Tumor cells induce the M1 macrophages to polarize to the M2‐type by releasing various factors, thereby inducing immune escape of cancer cells 114 . Exosomes are one of important signals released by tumor cells in this progression.…”

“…Tumor cells induce the M1 macrophages to polarize to the M2‐type by releasing various factors, thereby inducing immune escape of cancer cells. 114 Exosomes are one of important signals released by tumor cells in this progression. miRNAs are packaged into exosomes of cancer cells, and then transported to TAMs to promote M2 polarization.…”

Exosome-mediated communication between gastric cancer cells and macrophages: implications for tumor microenvironment

“…As a result, further comprehension of the interaction of TAM with tumor cells and the specific mechanism of immunosuppression in TME can help optimize the therapeutic regimen, and disrupting the malignant interactions between TAM and tumor cells can benefit and inhibit tumor progression. TAM is a vital part of the tumor microenvironment of GCs, influencing the malignant biological behaviors of GCs and playing an important role in the genesis and metastasis of GCs ( 174 – 176 ). In the tumor microenvironment, TAM produces a lot of inflammatory factors, growth factors, chemokines, and proteases through mutual crosstalk with GC cells and a variety of other cells, which play active roles in tumor growth, inhibition of apoptosis, angiogenesis, and lymphatic metastasis ( 177 – 179 ).…”