Rewiring exhausted CD8⁺ T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells are epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as Tex cells transition from progenitor (Tex^prog) to intermediate (Tex^int) and terminal (Tex^term) subsets, suggesting development flexibility. We examined epigenetic transitions between Tex cell subsets and revealed a reciprocally antagonistic circuit between Stat5a and Tox. Stat5 directed Tex^int cell formation and re-instigated partial effector biology during this Tex^prog-to-Tex^int cell transition. Constitutive Stat5a activity antagonized Tox and rewired CD8⁺ T cells from exhaustion to a durable effector and/or natural killer (NK)-like state with superior anti-tumor potential. Temporal induction of Stat5 activity in Tex cells using an orthogonal IL-2:IL2Rβ-pair fostered Tex^int cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partially reprogrammed the epigenetic landscape of exhaustion and restored polyfunctionality. These data highlight therapeutic opportunities of manipulating the IL-2-Stat5 axis to rewire Tex cells toward more durably protective states.

将耗竭的 CD8⁺ T （Tex） 细胞重新连接到功能状态仍然是一项治疗挑战。Tex 细胞由转录因子 Tox 表观遗传编程。然而，当 Tex 细胞从祖细胞 （Tex^prog） 转变为中间 （Tex^int） 和末端 （Tex^term） 亚群时，会发生表观遗传重塑，这表明发育具有灵活性。我们检查了 Tex 细胞亚群之间的表观遗传转换，并揭示了 Stat5a 和 Tox 之间的相互拮抗回路。Stat5 指导 Tex^int 细胞形成，并在 Tex^{prog-to-Tex int} 细胞转换期间重新激发部分效应子生物学。组成型 Stat5a 活性拮抗毒毒素并将 CD8⁺ T 细胞从耗竭重新连接为具有卓越抗肿瘤潜力的持久效应和/或自然杀伤 （NK） 样状态。使用正交 IL-2：IL2Rβ 对在 Tex 细胞中时间诱导 Stat5 活性促进了 Tex^int 细胞的积累，尤其是在 PD-L1 阻断后。重新参与 Stat5 还部分重新编程了耗竭的表观遗传景观并恢复了多功能。这些数据强调了操纵 IL-2-Stat5 轴以将 Tex 细胞重新连接至更持久的保护状态的治疗机会。