Metabolic and epigenetic orchestration of (CAR) T cell fate and function

Longevity, functionality, and metabolic fitness are key determinants of chimeric antigen receptor (CAR) T cell efficacy. Activated T cells follow an ordered differentiation program which is facilitated by metabolic adaptations. In response to antigen, T cells undergo a highly-regulated shift to glycolysis. Committing to, and engaging in, glycolysis supports T cell expansion and effector function. Inside tumors, heightened tumor cell metabolism and dysregulated perfusion create a competition for nutrients. As local metabolism supports the differentiation of T cells into functionally-competent progeny, nutrient depletion coupled with persisting antigen can trigger T cell exhaustion. Emerging insights into the barriers impeding CAR T cell function in hostile tumor microenvironments (TME) reveal that metabolic intermediates shape the immune response by influencing epigenetic programs and the control of gene expression. In this review, we discuss recent progress connecting cellular metabolism with epigenetic states in CAR T cells. Given that CAR T cell metabolism can be dynamically regulated, we introduce the concepts of "metabolic-based epigenetic altering" and "epigenetic-based metabolism altering" to restore functional competence in CARTs traversing solid TMEs.