Metabolic challenges and interventions in CAR T cell therapy

Chimeric antigen receptor (CAR) T cells have achieved true clinical success in treating hematological malignancy patients, laying the foundation of CAR T cells as a new pillar of cancer therapy. Although these promising effects have generated strong interest in expanding the treatment of CAR T cells to solid tumors, reproducible demonstration of clinical efficacy in the setting of solid tumors has remained challenging to date. Here, we review how metabolic stress and signaling in the tumor microenvironment, including intrinsic determinants of response to CAR T cell therapy and extrinsic obstacles, restrict the efficacy of CAR T cell therapy in cancer treatment. In addition, we discuss the use of novel approaches to target and rewire metabolic programming for CAR T cell manufacturing. Last, we summarize strategies that aim to improve the metabolic adaptability of CAR T cells to enhance their potency in mounting antitumor responses and survival within the tumor microenvironment.

Automated summary

Chimeric antigen receptor (CAR) T cells have achieved clinical success in treating hematological malignancy, but their efficacy in solid tumors remains challenging. This article reviews the metabolic stress and signaling in the tumor microenvironment that restrict the efficacy of CAR T cell therapy, and discusses novel approaches to target and rewire metabolic programming for CAR T cells. Strategies to improve the metabolic adaptability of CAR T cells and enhance their antitumor responses are also summarized.