Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)-T Cells

Simple Summary We review the mechanisms of cellular metabolism and mitochondrial function that have potential to impact on the success of chimeric antigen receptor (CAR) T cell therapy. The review focuses readers on mitochondrial functions to allow a better understanding of the complexity of T cell metabolic pathways, energetics and apoptotic/antiapoptotic pathways occurring in CAR T cells. We highlight potential modifications of T cell metabolism and mitochondrial function for the benefit of improved adoptive cellular therapy. Reprogramming metabolism in CAR T cells is an attractive approach to improve antitumour functions, increase persistence and enable adaptation to the nutrient-restricted solid tumour environment. Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours.