Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy

Cancer immunotherapy is an increasingly successful strategy for the treatment of patients who have advanced or conventional therapy-resistant cancers. T cells are key mediators of tumor destruction and their specificity for tumor-expressed antigens is of paramount importance, but other T cell-intrinsic qualities, such as durability, longevity, and functionality also play important roles in determining the efficacy of immunotherapy. The cellular energetic pathways that are utilized by T cells play a key role in regulating each of these qualities. Metabolic activity, which both regulates and is regulated by cellular signaling pathways and epigenetics, also profoundly influences the trajectories of T cell differentiation and fate. In this Review, we discuss how cell metabolism influences T cell anti-tumor activity, the metabolic qualities of highly-functional T cells, and strategies to modulate metabolism for improving the immune response to tumors. Does metabolism determine the fate of T cells? Kishton et al. review the relationships between metabolism, aging, and epigenetics in T cells, which are at the heart of new cancer immunotherapies. By manipulating key metabolic pathways, the efficacy of T cells can be improved in the setting of cancer immunotherapy.