Kang Tae Gun, Johnson Jordan T, Zebley Caitlin C, Youngblood Ben
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN, USA.
Nat Rev Cancer. 2026 Jan;26(1):46-61. doi: 10.1038/s41568-025-00883-y. Epub 2025 Oct 27.
Current T cell-based immunotherapy strategies, including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells, have revolutionized cancer care. However, many patients with cancer who are treated with these approaches fail to respond or do not achieve durable protection against disease relapse, highlighting the need for further optimization of such strategies. The advent of cancer immunotherapy has ushered in an era of research centred on immune oncology with a specific focus on defining T cell-intrinsic mechanisms that delineate therapeutic responders and non-responders. Among the major barriers limiting immunotherapy efficacy, T cell exhaustion - which is characterized by repression of the effector functions and proliferative potential of T cells - has emerged as a common mechanism among various cancers. Here, we review transcriptional and epigenetic mechanisms that control T cell exhaustion. We discuss how T cell subset-specific gene regulatory programmes limit immunotherapy success and theorize on the development of next-generation strategies for increasing the clinical breadth, efficacy and durability of T cell immunotherapy.
当前基于T细胞的免疫治疗策略，包括免疫检查点阻断（ICB）和嵌合抗原受体（CAR）T细胞，已经彻底改变了癌症治疗。然而，许多接受这些方法治疗的癌症患者没有反应或未能获得持久的疾病复发保护，这凸显了进一步优化此类策略的必要性。癌症免疫治疗的出现开创了一个以免疫肿瘤学为中心的研究时代，特别关注定义区分治疗反应者和无反应者的T细胞内在机制。在限制免疫治疗疗效的主要障碍中，T细胞耗竭——其特征是T细胞效应功能和增殖潜力受到抑制——已成为各种癌症中的一种常见机制。在这里，我们综述了控制T细胞耗竭的转录和表观遗传机制。我们讨论了T细胞亚群特异性基因调控程序如何限制免疫治疗的成功，并对开发提高T细胞免疫治疗临床广度、疗效和持久性的下一代策略进行了理论探讨。
