线粒体异柠檬酸脱氢酶通过限制抗氧化代谢和组蛋白乙酰化阻碍 CAR-T 细胞功能

The efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived memory CAR T cells are critical for improving tumor clearance and long-term protection.

However, during rapid ex vivo expansion or in vivo tumor eradication, metabolic shifts and inhibitory signals lead to terminal differentiation and exhaustion of CAR T cells. Through a mitochondria-related compound screening, we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances memory CAR T cell formation and sustains anti-leukemic cytotoxicity in vivo.

Mechanistically, IDH2 impedes metabolic fitness of CAR T cells by restraining glucose utilization via the pentose phosphate pathway, which alleviates oxidative stress, particularly in nutrient-restricted conditions.

In addition, IDH2 limits cytosolic acetyl-CoA levels to prevent histone acetylation that promotes memory cell formation. In combination with pharmacological IDH2 inhibition, CAR T cell therapy is demonstrated to have superior efficacy in a pre-clinical model.