Huang Yuwei, Wang Haopeng
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Lingang Laboratory, Shanghai, 200031, China.
Front Med. 2025 Mar 21. doi: 10.1007/s11684-025-1130-x.
Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in treating hematological malignancies and is expanding into other indications such as autoimmune diseases, fibrosis, aging and viral infection. However, clinical challenges persist in treating solid tumors, including physical barriers, tumor heterogeneity, poor in vivo persistence, and T-cell exhaustion, all of which hinder therapeutic efficacy. This review focuses on the critical role of tonic signaling in CAR-T therapy. Tonic signaling is a low-level constitutive signaling occurring in both natural and engineered antigen receptors without antigen stimulation. It plays a pivotal role in regulating immune cell homeostasis, exhaustion, persistence, and effector functions. The "Peak Theory" suggests an optimal level of tonic signaling for CAR-T function: while weak tonic signaling may result in poor proliferation and persistence, excessively strong signaling can cause T cell exhaustion. This review also summarizes the recent progress in mechanisms underlying the tonic signaling and strategies to fine-tune the CAR tonic signaling. By understanding and precisely modulating tonic signaling, the efficacy of CAR-T therapies can be further optimized, offering new avenues for treatment across a broader spectrum of diseases. These findings have implications beyond CAR-T cells, potentially impacting other engineered immune cell therapies such as CAR-NK and CAR-M.
嵌合抗原受体（CAR）T细胞疗法在治疗血液系统恶性肿瘤方面已显示出显著疗效，并正在扩展到其他适应症，如自身免疫性疾病、纤维化、衰老和病毒感染。然而，在治疗实体瘤时，临床挑战依然存在，包括物理屏障、肿瘤异质性、体内持久性差以及T细胞耗竭，所有这些都阻碍了治疗效果。本综述重点关注张力信号在CAR-T治疗中的关键作用。张力信号是在无抗原刺激的天然和工程化抗原受体中发生的低水平组成性信号。它在调节免疫细胞稳态、耗竭、持久性和效应功能方面起着关键作用。“峰值理论”表明CAR-T功能存在一个最佳的张力信号水平：弱张力信号可能导致增殖和持久性差，而信号过强则会导致T细胞耗竭。本综述还总结了张力信号相关机制的最新进展以及微调CAR张力信号的策略。通过理解和精确调节张力信号，可以进一步优化CAR-T疗法的疗效，为更广泛的疾病治疗提供新途径。这些发现不仅对CAR-T细胞有影响，还可能影响其他工程化免疫细胞疗法，如CAR-NK和CAR-M。
