BACH2 regulates T cell lineage state to enhance CAR T cell function

作者：Tien-Ching Chang, Amanda Heard, John Lattin, John M. Warrington, Amanda Barrett, Jack H. Landmann, Yangdon Tenzin, Vishaal Ganesh, Bryant Thompson, Sadia Afrin, Deepesh Kumar Gupta, Ju-Fang Chang, Julie Ritchey, Mehmet Emrah Selli, Yu-Sung Hsu, Haorui Song, A. J. Federico, Avery Horn, Michael P. Meers, Evan W. Weber, Thomas J. Wandless, Jeremy Chase Crawford, Paul G. Thomas, John F. DiPersio, Stephen Gottschalk, Nathan Singh · 发表于：Nature Immunology · 年份：2026 · DOI：10.1038/s41590-025-02391-5 · 被引用次数：11 · 研究领域：CAR-T cell therapy research、Monoclonal and Polyclonal Antibodies Research、T-cell and B-cell Immunology

Nearly all chimeric antigen receptors (CARs) signal in the absence of antigen, referred to as 'tonic signaling'. Tonic signaling of CARs containing 41BB domains enhances T cell fitness and function, in contrast to the exhaustion driven by CD28-containing CARs. Here we show that 41BB induces BACH2, a transcriptional regulator that directs stem and memory programs. Overexpression of BACH2 successfully prevented exhaustion but locked CAR T cells in a quiescent state. We linked BACH2 to a degradation domain to tune BACH2, enabling us to prevent exhaustion while enabling potent effector function that broadly enhanced the long-term efficacy of CAR T cells targeting liquid and solid tumors. Through interrogation of clinical CAR products, we further found an association between BACH2 activity and clinical outcomes in patients with leukemia. These data identify a central function for BACH2 in regulating CAR T cell efficacy.