功能持续性不佳限制了过继性 T 细胞疗法的功效。基于 CD28 的嵌合抗原受体 (CAR) 为 T 细胞赋予有效的效应功能，但寿命有限。我们在此表明​​，编码组蛋白 3、赖氨酸 9 甲基转移酶的 SUV39H1 的基因破坏增强了人类 CAR T 细胞在白血病和前列腺癌中的早期扩增、长期持久性和整体抗肿瘤功效楷模。持久性 SUV39H1 编辑的 CAR T 细胞在多次重新攻击后表现出改善的扩增和肿瘤排斥。反复攻击的 CAR T 细胞的转录和基因组可及性分析显示，SUV39H1 编辑的 CAR T 细胞中记忆转录因子的表达和可及性有所改善。 SUV39H1 编辑还可以减少抑制性受体的表达，并限制经历多次再攻击的 CAR T 细胞的耗竭。因此，我们的研究结果证明了 CAR T 细胞的表观遗传编程具有平衡其功能和持久性以改善过继性细胞疗法的潜力。

Suboptimal functional persistence limits the efficacy of adoptive T cell therapies. CD28-based chimeric antigen receptors (CARs) impart potent effector function to T cells but with a limited lifespan. We show here that the genetic disruption of SUV39H1, which encodes a histone-3, lysine-9 methyl-transferase, enhances the early expansion, long-term persistence, and overall anti-tumor efficacy of human CAR T cells in leukemia and prostate cancer models. Persisting SUV39H1-edited CAR T cells demonstrate improved expansion and tumor rejection upon multiple rechallenges. Transcriptional and genome accessibility profiling of repeatedly challenged CAR T cells shows improved expression and accessibility of memory transcription factors in SUV39H1-edited CAR T cells. SUV39H1 editing also reduces expression of inhibitory receptors and limits exhaustion in CAR T cells that have undergone multiple rechallenges. Our findings thus demonstrate the potential of epigenetic programming of CAR T cells to balance their function and persistence for improved adoptive cell therapies.