Metabolic crosstalk in the tumor microenvironment regulates antitumor immunosuppression and immunotherapy resisitance

Abstract

The successful treatment of human cancers by immunotherapy has been made possible by breakthroughs in the discovery of immune checkpoint regulators, including CTLA-4 and PD-1/PD-L1. However, the immunosuppressive effect of the tumor microenvironment still represents an important bottleneck that limits the success of immunotherapeutic approaches. The tumor microenvironment influences the metabolic crosstalk between tumor cells and tumor-infiltrating immune cells, creating competition for the utilization of nutrients and promoting immunosuppression. In addition, tumor-derived metabolites regulate the activation and effector function of immune cells through a variety of mechanisms; in turn, the metabolites and other factors secreted by immune cells can also become accomplices to cancer development. Immune-metabolic checkpoint regulation is an emerging concept that is being studied with the aim of restoring the immune response in the tumor microenvironment. In this review, we summarize the metabolic reprogramming of various cell types present in the tumor microenvironment, with a focus on the interaction between the metabolic pathways of these cells and antitumor immunosuppression. We also discuss the main metabolic checkpoints that could provide new means of enhancing antitumor immunotherapy.

Keywords: Antitumor immunotherapy; Immune checkpoint; Metabolic checkpoint; Metabolic reprogramming; Tumor metabolism.

Fig. 1

Overview of the complex interactions between tumor cells and immune cells and the metabolic characteristics of these cells. During tumorigenesis and malignant progression, a complex intercellular interaction network is established between tumor-infiltrated immune cells and tumor cells that improves and maintains the immunosuppressive microenvironment and promotes immune escape. Black arrow recruit or promote, Pink T-line inhibit, Red up arrow upregulate, Red down arrow downregulate, TME tumor microenvironment, TAM tumor-associated macrophage, Treg regulatory T cell, DC dendritic cell, MDSC myeloid-derived suppressor cell

Fig. 2

Metabolic competition and tumor-derived metabolite-mediated immunosuppression in the tumor microenvironment. Tumor cells compete with immune cells to preferentially utilize glucose and glutamine in the microenvironment. Tumor-derived metabolites, such as lactate, PGE2 and K⁺, can inhibit T cell movement, effector function and TAM polarization and promote stemness, ultimately promoting immune escape

Fig. 3

Modulation of T cell-mediated antitumor immunity by targeting metabolic checkpoints. Targeted inhibition of metabolic checkpoints, such as IDO, ACAT1, CD39, CD73 and A2A, can enhance the antitumor effects of T cells. IDO indoleamine 2,3-dioxygenase, ACAT1 acetyl-CoA acetyltransferase 1