Current immunotherapies yield remarkable clinical outcomes by boosting the power of host immunity in cancer cell elimination and viral clearance. However, after prolonged antigen exposure, CD8⁺ T cells differentiate into a special differentiation state known as T-cell exhaustion, which poses one of the major hurdles to antiviral and antitumor immunity during chronic viral infection and tumour development. Growing evidence indicates that exhausted T cells undergo metabolic insufficiency with altered signalling cascades and epigenetic landscapes, which dampen effector immunity and cause poor responsiveness to immune-checkpoint-blockade therapies. How metabolic stress affects T-cell exhaustion remains unclear; therefore, in this Review, we summarize current knowledge of how T-cell exhaustion occurs, and discuss how metabolic insufficiency and prolonged stress responses may affect signalling cascades and epigenetic reprogramming, thus locking T cells into an exhausted state via specialized differentiation programming.

目前的免疫疗法通过增强宿主免疫在癌细胞消除和病毒清除方面的能力，产生了显着的临床效果。然而，长时间接触抗原后，CD8 ⁺T 细胞分化成一种特殊的分化状态，称为 T 细胞衰竭，这是慢性病毒感染和肿瘤发展过程中抗病毒和抗肿瘤免疫的主要障碍之一。越来越多的证据表明，疲惫的 T 细胞会出现代谢不足，信号级联和表观遗传景观发生改变，这会抑制效应免疫并导致对免疫检查点阻断疗法的反应不佳。代谢压力如何影响 T 细胞耗竭仍不清楚；因此，在这篇综述中，我们总结了当前关于 T 细胞衰竭如何发生的知识，并讨论了代谢不足和长期应激反应如何影响信号级联和表观遗传重编程，从而通过专门的分化编程将 T 细胞锁定在衰竭状态。