免疫治疗是治疗癌症的一项显著临床进展。 T细胞是当前癌症免疫治疗的关键，包括免疫检查点抑制剂和移植细胞疗法。然而，癌症与T细胞耗竭有关，这是一种低功能状态，其特征是T细胞效应子功能和自我更新能力不断丧失。 “去除”肿瘤微环境中的T细胞通常被认为是免疫检查点抑制剂的关键作用机制，并且T细胞耗竭被认为是细胞免疫疗法的一条耐药途径。几项精妙的研究提供了关于调控T细胞耗竭的转录和表观遗传程序的重要见解。在这篇综述中，我们重点介绍了与T细胞耗竭免疫生物学相关的最新发现，这些发现提供了比完全不良状态更为细致的视角。我们回顾了T细胞耗竭可能是良性肿瘤控制的反应，而不仅是其原因的证据。此外，我们提出假设，在某些慢性抗原刺激的情况下，中断耗竭程序可能会损害T细胞的持久性。因此，优先考虑减轻T细胞耗竭的干预措施，包括正交细胞还原疗法和新型细胞工程策略，最终可能会产生更好的临床结果和癌症免疫疗法的最大进展。 ©2022 Springer Nature Limited.

Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity. The 'un-exhausting' of T cells in the tumour microenvironment is commonly regarded as a key mechanism of action for immune-checkpoint inhibitors, and T cell exhaustion is considered a pathway of resistance for cellular immunotherapies. Several elegant studies have provided important insights into the transcriptional and epigenetic programmes that govern T cell exhaustion. In this Review, we highlight recent discoveries related to the immunobiology of T cell exhaustion that offer a more nuanced perspective beyond this hypofunctional state being entirely undesirable. We review evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control. Furthermore, we hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence. Therefore, the prioritization of interventions that mitigate the development of T cell exhaustion, including orthogonal cytoreduction therapies and novel cellular engineering strategies, might ultimately confer superior clinical outcomes and the greatest advances in cancer immunotherapy.© 2022. Springer Nature Limited.