CD8 T 细胞效应功能的逐渐衰退（也称为终末耗竭）是癌症免疫逃避的主要原因。然而，驱动 CD8 T 细胞功能障碍的分子机制仍知之甚少。在这里，我们报道了 Kelch 样 ECH 相关蛋白 1 (KEAP1)-核因子红细胞 2 相关因子 2 (NRF2) 信号轴，介导细胞对氧化应激的适应，直接调节 CD8 T 细胞耗竭。对慢性感染和癌症导致的功能失调的 CD8 T 细胞的转录谱揭示了终末耗竭（Tex 术语）CD8 T 细胞中 NRF2 活性的富集。增加 CD8 T 细胞中的 NRF2 活性（通过条件性删除 KEAP1）可促进谷胱甘肽生成和抗氧化防御增加，同时加速最终耗尽 (PD-1 TIM-3 ) CD8 T 细胞的发育，以应对慢性感染或肿瘤挑战。从机制上讲，我们将循环类二十烷酸前列环素的受体 PTGIR 确定为一种 NRF2 调节蛋白，可促进 CD8 T 细胞功能障碍。沉默 PTGIR 表达可恢复 KEAP1 缺陷 T 细胞的抗肿瘤功能。此外，降低 CD8 T 细胞中的 PTGIR 表达既可以减少终末耗竭，又可以增强 T 细胞对慢性感染和癌症的效应反应（即 IFN-γ 和颗粒酶的产生）。总之，这些结果确立了 KEAP1-NRF2 轴作为将氧化应激与 CD8 T 细胞功能障碍联系起来的代谢传感器，并将前列环素受体 PTGIR 确定为 NRF2 调节的免疫检查点，调节效应器和耗尽状态之间的 CD8 T 细胞命运决定。 -NRF2 通路在最终耗尽的 CD8 T 细胞中过度激活，并通过前列环素受体 Ptgir 的转录调节驱动 T 细胞功能障碍。

The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Tex term ) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1 + TIM-3 + ) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.The KEAP1-NRF2 pathway is hyperactivated in terminally exhausted CD8 T cells and drives T cell dysfunction via transcriptional regulation of the prostacyclin receptor, Ptgir .