Engineering mitochondrial adaptability of CAR-T cells for cancer immunotherapy: mechanisms, therapeutic strategies, and translational opportunities

Background Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of selected hematologic malignancies, but limited persistence, progressive exhaustion, and inadequate adaptation to the metabolically restrictive tumor microenvironment continue to constrain durable efficacy, particularly in solid tumors. Mitochondrial adaptability, encompassing bioenergetic output, redox homeostasis, substrate use, organelle dynamics, and quality control, is increasingly recognized as a determinant of CAR-T cell expansion, functional recovery, and persistence. Main body This review integrates direct CAR-T evidence with mechanistic findings from conventional T cells to examine how mitochondrial remodeling governs activation, memory-associated persistence, and exhaustion. Hypoxia, nutrient competition, lactate accumulation and acidosis, adenosine signaling, lipid stress, tumor-derived metabolites, and chronic antigen exposure progressively impair respiratory reserve and metabolic flexibility. CAR architecture also establishes intrinsic metabolic demand through the recognition domain, transmembrane region, costimulatory module, and CD3-proximal signaling. Current optimization strategies include metabolic programming during manufacturing, transient pharmacologic conditioning, genetic reinforcement of respiration, substrate acquisition, redox control, and organelle quality, receptor and cytokine-circuit engineering, and mitochondrial transfer. Patient-derived studies associate mitochondrial features of infusion products with expansion and clinical response, while early clinical studies of cytokine-armored products indicate translational potential. However, most interventional evidence remains preclinical, and longitudinal mitochondrial target engagement in patient-derived CAR-positive cells has rarely been demonstrated. In addition, this review discusses approaches to assessing mitochondrial adaptability in CAR-T cells before and after infusion and their potential integration with functional potency assays. Potential liabilities include excessive activation, cytokine-related toxicity, amplification of on-target, off-tumor injury, oxidative stress, altered immune regulation, and manufacturing complexity. Conclusion Effective mitochondrial optimization requires matching the intervention to when and why dysfunction arises, while accounting for tumor metabolism and CAR signaling. Embedding this precision within a controllable and clinically tractable development framework may enable next-generation CAR-T cells with greater persistence, metabolic resilience, and translational potential. Clinical trial number Not applicable.