CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction

Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a transformative advancement in cancer immunotherapy, but remains limited by multiple challenges. The exhaustion of T cells represents a critical obstacle limiting the success of immunotherapeutic interventions. Targeting mitochondrial metabolism offers a promising approach to mitigate exhaustion and enhance CAR-T persistence. Mechanistically, mitochondrial dysfunction within the tumor microenvironment disrupts energy metabolism, reactive oxygen species (ROS) homeostasis, and cell survival, impairing CAR-T function. Here, we review the current challenges facing the clinical application of CAR-T therapy in cancers and summarize mitochondrial-centered approaches to overcome some of these obstacles by optimizing mitochondrial metabolic pathways. We emphasize the essential role of mitochondrial metabolism in augmenting therapeutic efficacy and persistence of CAR-T cells. Future breakthroughs will depend on robust clinical evidence and precise metabolic modulation to enhance CAR-T therapies.