Multiple myeloma remains incurable, and although BCMA CAR-T therapy induces deep responses, most patients eventually relapse due to T-cell exhaustion, limited CAR-T persistence, and metabolic stress in the tumor microenvironment. Activated T-cells are vulnerable to ferroptosis, a form of cell death driven by glutathione depletion, oxidative stress, and CHAC1 activity. Enhancing redox resilience improves CAR-T durability. IRX4204, a selective RXR agonist, protected CAR-T cells from T-cell exhaustion and ferroptotic death, thereby enhancing their persistence and anti-tumor function. Mechanistically, IRX4204 suppresses CHAC1-driven ferroptosis and activates PINK1/PARK2-mediated mitophagy, preserving mitochondrial integrity. In vivo, IRX4204 improved tumor control and prolonged CAR-T persistence in multiple myeloma xenografts.






