Regenerative stem cell–like memory (T_SCM) CD8⁺ T cells persist longer and produce stronger effector functions. We found that MEK1/2 inhibition (MEKi) induces T_SCM that have naive phenotype with self-renewability, enhanced multipotency and proliferative capacity. This is achieved by delaying cell division and enhancing mitochondrial biogenesis and fatty acid oxidation, without affecting T cell receptor-mediated activation. DNA methylation profiling revealed that MEKi-induced T_SCM cells exhibited plasticity and loci-specific profiles similar to bona fide T_SCM isolated from healthy donors, with intermediate characteristics compared to naive and central memory T cells. Ex vivo, antigenic rechallenge of MEKi-treated CD8⁺ T cells showed stronger recall responses. This strategy generated T cells with higher efficacy for adoptive cell therapy. Moreover, MEKi treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects. In conclusion, we show that MEKi leads to CD8⁺ T cell reprogramming into T_SCM that acts as a reservoir for effector T cells with potent therapeutic characteristics.

再生干细胞样记忆 (T _SCM ) CD8 ⁺ T 细胞持续时间更长，并产生更强的效应功能。我们发现 MEK1/2 抑制 (MEKi) 诱导 T _SCM，其具有具有自我更新能力、增强的多能性和增殖能力的幼稚表型。这是通过延迟细胞分裂和增强线粒体生物发生和脂肪酸氧化来实现的，而不影响 T 细胞受体介导的激活。DNA 甲基化分析表明，MEKi 诱导的 T _SCM细胞表现出与真正的 T _{SCM相似的可塑性和位点特异性特征}从健康供体中分离出来，与幼稚和中央记忆 T 细胞相比具有中间特征。离体，MEKi 处理的 CD8 ⁺ T 细胞的抗原再攻击显示出更强的回忆反应。该策略生成的 T 细胞对过继细胞疗法具有更高的疗效。此外，MEKi 治疗荷瘤小鼠也显示出强烈的免疫介导的抗肿瘤作用。总之，我们表明 MEKi 导致 CD8 ⁺ T 细胞重编程为 T _SCM，T SCM 充当具有有效治疗特性的效应 T 细胞的储库。