T细胞耗竭是指T细胞因持续的抗原刺激而出现功能受损的进行性状态，其特征是免疫抑制受体表达增加，但效应功能减弱，自我更新能力降低，表观遗传学、转录程序和代谢改变。 T细胞耗竭是导致癌症免疫逃逸的主要原因之一，它创造了支持肿瘤发展和转移扩散的环境。此外，T 细胞耗竭对于当前癌症免疫疗法的疗效起着关键作用。本综述旨在全面了解 T 细胞耗竭在癌症发生和进展中的作用。我们总结了参与T细胞耗竭的调节机制，包括转录因子、表观遗传和代谢重编程事件，以及各种微环境因素，如细胞因子、微生物和肿瘤自分泌物质。论文还讨论了 T 细胞耗竭给癌症免疫疗法带来的挑战，包括免疫检查点阻断（ICB）疗法和嵌合抗原受体 T 细胞（CAR-T）疗法，强调了 ICB 疗法和 CAR-T 疗法由于以下原因遇到的障碍： T 细胞耗竭。最后，本文概述了当前 ICB 和 CAR-T 疗法中旨在逆转或减轻 T 细胞耗竭的治疗方案。这些治疗方法旨在克服 T 细胞衰竭并增强免疫疗法治疗肿瘤的有效性。版权所有 © 2024。由 Elsevier B.V. 出版。

T cell exhaustion refers to a progressive state in which T cells become functionally impaired due to sustained antigenic stimulation, which is characterized by increased expression of immune inhibitory receptors, but weakened effector functions, reduced self-renewal capacity, altered epigenetics, transcriptional programme and metabolism. T cell exhaustion is one of the major causes leading to immune escape of cancer, creating an environment that supports tumor development and metastatic spread. In addition, T cell exhaustion plays a pivotal role to the efficacy of current immunotherapies for cancer. This review aims to provide a comprehensive view of roles of T cell exhaustion in cancer development and progression. We summerized the regulatory mechanisms that involved in T cell exhaustion, including transcription factors, epigenetic and metabolic reprogramming events, and various microenvironmental factors such as cytokines, microorganisms, and tumor autocrine substances. The paper also discussed the challenges posed by T cell exhaustion to cancer immunotherapies, including immune checkpoint blockade (ICB) therapies and chimeric antigen receptor T cell (CAR-T) therapy, highlightsing the obstacles encountered in ICB therapies and CAR-T therapies due to T cell exhaustion. Finally, the article provides an overview of current therapeutic options aimed to reversing or alleviating T cell exhaustion in ICB and CAR-T therapies. These therapeutic approaches seek to overcome T cell exhaustion and enhance the effectiveness of immunotherapies in treating tumors.Copyright © 2024. Published by Elsevier B.V.