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 expansion or 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 . 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.

中文翻译：

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线粒体异柠檬酸脱氢酶通过抑制抗氧化代谢和组蛋白乙酰化来阻碍 CAR T 细胞功能

嵌合抗原受体 (CAR) T 细胞疗法的疗效受到血液恶性肿瘤复发和实体瘤反应低下的影响。长寿命记忆 CAR T 细胞对于改善肿瘤清除和长期保护至关重要。然而，在肿瘤快速扩张或根除过程中，代谢变化和抑制信号会导致 CAR T 细胞的终末分化和耗竭。通过线粒体相关化合物筛选，我们发现FDA批准的异柠檬酸脱氢酶2（IDH2）抑制剂enasidenib可增强记忆CAR T细胞形成并维持抗白血病细胞毒性。从机制上讲，IDH2 通过磷酸戊糖途径抑制葡萄糖利用，从而阻碍 CAR T 细胞的代谢适应性，从而减轻氧化应激，特别是在营养受限的条件下。此外，IDH2 限制胞质乙酰辅酶 A 水平，以防止促进记忆细胞形成的组蛋白乙酰化。与药理学 IDH2 抑制相结合，CAR T 细胞疗法在临床前模型中被证明具有卓越的疗效。