Reprogramming T-cell metabolism to enhance adoptive cell therapies

Adoptive cell therapy (ACT) is an immunotherapeutic approach that involves isolating T cells from a patient, culturing them ex vivo, then reinfusing the cells back into the patient. Although this strategy has shown remarkable efficacy in hematological malignancies, the solid-tumour microenvironment (TME) has presented serious challenges for therapy efficacy. Particularly, the TME has immunosuppressive signalling and presents a metabolically challenging environment that leads to T-cell suppression. T-cell metabolism is an expanding field of research with a focus on understanding its inherent link to T-cell function. Here, we review the current model of T-cell metabolism from naive cells through effector and memory life stages, as well as updates to the model from recent literature. These models of metabolism have provided us with the tools and understanding to explore T-cell metabolic and mitochondrial insufficiency in the TME. We discuss manipulations that can be made to these mitochondrial and metabolic pathways to enhance the persistence of infused T cells, overcome the metabolically challenging TME and improve the efficacy of therapy in ACT models. Further understanding and investigation of the impact of metabolic pathways on T-cell performance could contribute to improving therapy efficacy for patients. Graphical Abstract