稳健而有效的T细胞免疫监视和癌症免疫疗法需要合理配置代谢资源，以维持包括生长和细胞因子产生在内的耗能过程。在这里，我们展示了门控CD8+ T细胞上的天冬氨酸（Asn）限制在T细胞激活后的激活阶段和分化阶段产生了相反的作用。Asn限制抑制了早期阶段的激活和细胞周期进入，同时快速激发了红细胞生成2相关因子核因子2（NRF2）依赖的应激反应，在分化过程中为CD8+ T细胞提供了强大的增殖和效应功能。机制上，通过Asn限制在CD8+ T细胞中引发的NRF2激活通过降低整体葡萄糖和谷氨酰胺的消耗，但增加细胞内核苷酸的含量，从而促进增殖。因此，Asn限制或NRF2激活在临床前动物模型中增强了T细胞介导的抗肿瘤反应，表明Asn限制是一种有前景且临床相关的增强癌症免疫疗法的策略。我们的研究揭示了Asn作为调节应激信号传导以塑造T细胞代谢适应性和效应功能的关键代谢节点。© 2023年，本文作者。

Robust and effective T cell immune surveillance and cancer immunotherapy require proper allocation of metabolic resources to sustain energetically costly processes, including growth and cytokine production. Here, we show that asparagine (Asn) restriction on CD8+ T cells exerted opposing effects during activation (early phase) and differentiation (late phase) following T cell activation. Asn restriction suppressed activation and cell cycle entry in the early phase while rapidly engaging the nuclear factor erythroid 2-related factor 2 (NRF2)-dependent stress response, conferring robust proliferation and effector function on CD8+ T cells during differentiation. Mechanistically, NRF2 activation in CD8+ T cells conferred by Asn restriction rewired the metabolic program by reducing the overall glucose and glutamine consumption but increasing intracellular nucleotides to promote proliferation. Accordingly, Asn restriction or NRF2 activation potentiated the T cell-mediated antitumoral response in preclinical animal models, suggesting that Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy. Our study revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions.© 2023. The Author(s).