Cancer Cell Metabolism Bolsters Immunotherapy Resistance by Promoting an Immunosuppressive Tumor Microenvironment

Abstract

Immune checkpoint inhibitors (ICIs) targeting immune checkpoint proteins, such as CTLA-4 and PD-1/PD-L1, have demonstrated remarkable and durable clinical responses in various cancer types. However, a considerable number of patients receiving ICIs eventually experience a relapse due to diverse resistance mechanisms. As a result, there have been increasing research efforts to elucidate the molecular mechanisms behind resistance to ICIs and improve patient outcomes. There is growing evidence that the dysregulated metabolic activity of tumor cells generates an immunosuppressive tumor microenvironment (TME) that orchestrates an impaired anti-tumor immune response. Notably, the immunosuppressive TME is characterized by nutrient shortage, hypoxia, an acidic extracellular milieu, and abundant immunosuppressive molecules. A detailed understanding of the TME remains a major challenge in mounting a more effective anti-tumor immune response. Herein, we discuss how tumor cells reprogram metabolism to modulate a pro-tumor TME, driving disease progression and immune evasion; in particular, we highlight potential approaches to target metabolic vulnerabilities in the context of anti-tumor immunotherapy.

Keywords: cancer cell metabolite; cancer metabolism; immune checkpoint inhibitors; immune evasion; tumor microenvironment.

Figure 1

The tumor metabolic stress shapes an immunosuppressive the tumor microenvironment. An overview of metabolic stress in the TME that mediates immune suppression. In the TME, cancer cells exhibit a substantial demand of nutrients, including glucose, amino acids, and fatty acids, and this contributes to the lack of dioxygen and maintains high production of H⁺. These metabolic stresses promote tumor cell growth, increase the expression of immune checkpoint proteins and immunosuppressive cytokines secretion, enhance the inhibitory function of regulatory T cells, and inhibit the anti-tumor effect of tumor-infiltrating cytotoxic T cells, thereby leading to an immunosuppressive TME.

Figure 2

Tumor metabolites promote tumor immune evasion. Compared with other cell types, tumor cells display increased production of immunosuppressive metabolites, such as, adenosine, R-2-HG, glutamine, and methylglyoxal in the TME. These metabolites cause cytotoxic T cell anergy, increase the infiltration of MDSCs, and impair anti-tumor immunity.