Metabolic checkpoints and novel approaches for immunotherapy against cancer

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.