A Tonic Signaling Code Predicts CAR-T Cell Efficacy in Diffuse Midline Glioma.

ABSTRACT: Diffuse midline glioma (DIPG/DMG) is a uniformly fatal pediatric brain tumor with no effective cure. Although CAR T-cell therapy shows promise, clinical outcomes remain inconsistent due to limited persistence and premature exhaustion. Reliable predictive biomarkers are lacking, and proposed exhaustion or stemness markers provide limited utility. Here, we systematically compare multiple CAR-T constructs targeting clinically-relevant antigen B7-H3 and identify antigen-independent CAR activation, or tonic signaling, as a key determinant of therapeutic performance. We find that B7-H3 CAR-T cells with restrained tonic signaling display superior tumor killing, persistence, and resistance to exhaustion, along with reduced CAR membrane clustering, in patient-derived DIPG models. Integrated multi-o

SUBMITTER: Deng EB 

PROVIDER: S-EPMC12621713 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature