癌症患者过继性 T 细胞疗法的失败与有限的 T 细胞扩增和持久性有关，即使是在有记忆倾向的 41BB-(BBz) 嵌合抗原受体 (CAR) T 细胞中也是如此。我们在此表明​​，通过组蛋白 3 赖氨酸 9 三甲基化 (H3K9me3) 途径的表观遗传操作可以增强 BBz-CAR T 细胞干/记忆分化和持久性。 H3K9 三甲基转移酶 SUV39H1 的失活可增强 BBz-CAR T 细胞的长期持久性，保护小鼠在 CAR T 细胞输注后数月内免受肺部和播散性实体瘤模型中的肿瘤复发和再攻击。对肿瘤浸润 CAR T 细胞的单细胞转录组 (scRNAseq) 和染色质开放 (scATACseq) 分析显示，所有 T 细胞亚群中的功能障碍基因表达均降低，早期重编程为自我更新的干细胞样群体。因此，SUV39H1 对 H3K9 甲基化的表观遗传操作可优化 BBz-CAR T 细胞的长期功能持久性，限制复发并提供针对肿瘤再次攻击的保护。

Failure of adoptive T cell therapies in cancer patients is linked to limited T cell expansion and persistence, even in memory-prone 41BB-(BBz)-based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR T cell stem/memory differentiation and persistence can be enhanced through epigenetic manipulation of the histone 3 lysine 9 tri-methylation (H3K9me3) pathway. Inactivation of the H3K9 tri-methyltransferase SUV39H1 enhances BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated solid tumor models up to several months after CAR T cell infusion. Single-cell transcriptomic (scRNAseq) and chromatin opening (scATACseq) analyses of tumor infiltrating CAR T cells show early reprogramming into self-renewing, stem-like populations with decreased expression of dysfunction genes in all T cell subpopulations. Therefore, epigenetic manipulation of H3K9 methylation by SUV39H1 optimizes long-term functional persistence of BBz-CAR T cells, limiting relapses and providing protection against tumor rechallenges.