zeste 同源物 2 (EZH2) 的组蛋白甲基转移酶增强子在 T 细胞分化、增殖和功能中发挥重要作用。先前的研究表明，CD8 或总 T 细胞中 EZH2 的基因缺失会损害其抗病毒和抗肿瘤活性、细胞因子的产生以及再次攻击时的扩展能力。与删除 T 细胞固有的 EZH2 的有害作用相反，我们在这里证明，在表型衰竭之前，使用临床批准的抑制剂 Tazemetostat 对 T 细胞中的 EZH2 进行短暂抑制，可以延缓其功能失调的进展并保留 T 细胞的干性。和多功能性，但对细胞增殖没有负面影响。 Tazemetostat 诱导 T 细胞表观遗传重编程，并通过优先减少快速分裂 T 细胞中启动子 H3K27 甲基化来增加自我更新 T 细胞转录因子 TCF1 的表达。在小鼠黑色素瘤模型中，EZH2 耗尽的 T 细胞导致肿瘤控制不佳，而用他泽美司他预处理的过继转移 T 细胞表现出优异的抗肿瘤免疫力，尤其是与抗 PD-1 阻断剂联合使用时。总的来说，这些数据凸显了通过抑制 EZH2 进行瞬时表观遗传重编程以增强过继性 T 细胞免疫治疗的潜力。

The histone methyltransferase enhancer of zeste homolog 2 (EZH2) plays important roles in T-cell differentiation, proliferation and function. Previous studies have demonstrated that genetic deletion of EZH2 in CD8+ or total T cells impairs their antiviral and antitumor activity, cytokine production and ability to expand upon rechallenge. Contrary to the detrimental role of deleting T cell-intrinsic EZH2, here we have demonstrated that transient inhibition of EZH2 in T cells prior to the phenotypic onset of exhaustion with a clinically approved inhibitor, Tazemetostat, delayed their dysfunctional progression and preserved T-cell stemness and polyfunctionality but had no negative impact on cell proliferation. Tazemetostat induced T-cell epigenetic reprogramming and increased the expression of the self-renewal T-cell transcription factor TCF1 by reducing H3K27 methylation at its promoter preferentially in rapidly dividing T cells. In a murine melanoma model, T cells depleted of EZH2 induced poor tumor control, whereas adoptively transferred T cells pretreated with tazemetostat exhibited superior antitumor immunity, especially when used in combination with anti-PD-1 blockade. Collectively, these data highlight the potential of transient epigenetic reprogramming by EZH2 inhibition to enhance adoptive T-cell immunotherapy.