The full potential of T cell-based immunotherapies remains limited by a variety of T cell extrinsic and intrinsic immunosuppressive mechanisms that can become imprinted to stably reduce the antitumor ability of T cells. Here, we discuss recent insights into memory CD8⁺ T cell differentiation and exhaustion and the association of these differentiation states with clinical outcomes during immune checkpoint blockade and chimeric antigen receptor (CAR) T cell therapeutic modalities. We consider the barriers limiting immunotherapy with a focus on epigenetic regulation impeding efficacy of adoptively transferred T cells and other approaches that augment T cell responses such as immune checkpoint blockade. Furthermore, we outline conceptual and technical breakthroughs that can be applied to existing therapeutic approaches and to the development of novel cutting-edge strategies.

基于 T 细胞的免疫疗法的全部潜力仍然受到各种 T 细胞外在和内在免疫抑制机制的限制，这些机制可以被印记以稳定地降低 T 细胞的抗肿瘤能力。在这里，我们讨论了对记忆 CD8 ⁺ T 细胞分化和耗竭的最新见解，以及这些分化状态与免疫检查点阻断和嵌合抗原受体 (CAR) T 细胞治疗方式期间临床结果的关联。我们考虑了限制免疫治疗的障碍，重点是表观遗传调控，阻碍了过继转移 T 细胞的功效，以及其他增强 T 细胞反应的方法，例如免疫检查点阻断。此外，我们概述了可应用于现有治疗方法和开发新颖的前沿策略的概念和技术突破。