Mitochondrial engineering enhances CAR-T cell therapy for solid and blood cancers

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematological malignancies, yet its efficacy in solid tumors is severely limited by the metabolically hostile tumor microenvironment (TME). Within this landscape, CAR-T cells undergo rapid functional exhaustion driven by mitochondrial dysfunction and metabolic insufficiency. This mini-review synthesizes emerging mitochondrial engineering strategies designed to restore metabolic fitness and persistence. We first examine the newly identified metabolic-epigenetic axis, where the pathological mitochondrial translocation of P4HA1 and the concomitant accumulation of oncometabolite succinate lock T cells in an exhausted state, and discuss how targeting this pathway restores progenitor subsets. Furthermore, we explore genetic reprogramming approaches, including “Envirotune” platforms that couple hypoxia-sensing elements (HRE) with enhanced glutamine transport (SLC38A2), and CRISPR-identified targets such as RHOG and FAS that prevent fratricide and apoptosis to preserve effector pools. Finally, we highlight the frontier of organelle medicine, focusing on intercellular mitochondrial transfer via tunneling nanotubes (TNTs) mediated by Talin-2, and emerging computational strategies to detect mitochondrial hijacking risk. By integrating these metabolic interventions, next-generation CAR-T cells can be engineered to overcome the TME’s metabolic barriers, transforming them from transient effectors into long-lived, highly effective therapeutic agents.