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While immunotherapy has achieved unprecedented success in conquering cancer, the majority of patients develop primary or acquired resistance to immunotherapy, largely in part due to the complicated metabolic networks in the tumor microenvironment. The microenvironmental metabolic networks are woven by a set of metabolic checkpoints, and accumulating evidence indicates that these metabolic checkpoints orchestrate antitumor immunity and immunotherapy. Metabolic checkpoints can regulate T cell development, differentiation and function, orchestrate metabolic competition between tumor cells and infiltrating T cells, and respond to the metabolic stress imposed on the infiltrating T cells. Furthermore, metabolic checkpoints and pathways can modulate the expression profiles of immune checkpoint receptors and ligands and vice versa. Therefore, repurposing interventions targeting metabolic checkpoints might synergize with immunotherapy, and promising approaches to reprogram the metabolic environment are much more warranted. In this review, we summarize recent researches on the metabolic checkpoints and discuss how these metabolic checkpoints regulate antitumor immunity and the promising approaches to modulate these metabolic checkpoints in the combination therapy. A comprehensive and objective understanding of the metabolic checkpoints might help the research and development of novel approaches to antitumor immunotherapy., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Simple Summary: It has been known for decades that immune T cells, especially due to their capacity for powerful antigen-directed cytotoxicity, have become a central focus for engaging the immune system in the fight against cancer. Interest in harnessing T cells for cancer immunotherapy is rapidly growing. The latest clinical research aims to effectively use immune checkpoint inhibitor (ICI) drugs to treat cancer patients. However, T cells can either establish a protective antitumor response, or, in contrast, induce severe dysfunction that promotes disease progression in the majority of chronic infection patients. The contradiction depends, to a large degree, on the interaction between immune T cells and other tumor infiltrating cells or inflammatory cytokines around the tumor microenvironment. This review aims to summarize the current knowledge and regulatory mechanisms of CD8+T cell exhaustion, since reversing T cell exhaustion will definitely become a biomarker of clinical tumor immunotherapy. CD8+T cell exhaustion is a state of T cell dysfunction during chronic infection and tumor progression. Exhausted CD8+T cells are characterized by low effector function, high expression of inhibitory receptors, unique metabolic patterns, and altered transcriptional profiles. Recently, advances in understanding and interfering with the regulatory mechanisms associated with T cell exhaustion in tumor immunotherapy have brought greater attention to the field. Therefore, we emphasize the typical features and related mechanisms of CD8+T cell exhaustion and particularly the potential for its reversal, which has clinical implications for immunotherapy. [ABSTRACT FROM AUTHOR]