Remodeling metabolic fitness: Strategies for improving the efficacy of chimeric antigen receptor T cell therapy

The dramatic success of adoptive transfer of engineered T cells expressing chimeric antigen receptor (CAR-T) has been achieved with effective responses in some relapsed or refractory hematologic malignancies, which is not yet met in solid tumors. The efficacy of CAR-T therapy is associated with its fate determination and their interaction with cancer cells in tumor microenvironment (TME), which is closely correlated with T cell metabolism fitness. Indeed, modulating T cell metabolism reprogramming has been proven crucial for their survival and reinvigorating antitumor immunity, and thus is considered as a promising strategy to improve the clinical performance of CAR-T cell therapy in difficult-to-treat cancers. This review briefly summarizes the T cell metabolic profiles and key metabolic challenges it faces in TME such as nutrient depletion, hypoxia, and toxic metabolites, then emphatically discusses the potential strategies to modulate metabolic properties of CAR-T cells including improving CARs construct design, optimizing manufacture process via addition of exogenous cytokines or targeting specific signaling pathway, manipulating ROS levels balance or relieving the unfavorable metabolic TME including adaptation to hypoxia and blocking inhibitory effect of toxic metabolites, eventually strengthening the anti-tumor response.