Tonic signaling in CAR-T therapy: the lever long enough to move the planet.
10.1007/s11684-025-1130-x
- Author:
Yuwei HUANG
1
;
Haopeng WANG
2
Author Information
1. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
2. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. wanghp@shanghaitech.edu.cn.
- Publication Type:Review
- Keywords:
CAR signaling;
CAR-NK;
CAR-T;
CAR-macrophage;
antigen receptor;
tonic signal
- MeSH:
Humans;
Immunotherapy, Adoptive/methods*;
Receptors, Chimeric Antigen/immunology*;
Signal Transduction/immunology*;
T-Lymphocytes/immunology*;
Neoplasms/immunology*;
Animals
- From:
Frontiers of Medicine
2025;19(3):391-408
- CountryChina
- Language:English
-
Abstract:
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.
