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

ABSTRACT: Diffuse midline glioma (DIPG/DMG) is a uniformly fatal pediatric brain tumor. While CAR T-cell therapy holds promise, clinical responses remain inconsistent, largely due to limited CAR-T persistence and premature exhaustion. Reliable biomarkers to predict therapeutic efficacy are lacking, and proposed T-cell exhaustion or stemness markers offer limited predictive value. Here, we systematically evaluate CAR-T cells against the clinically relevant tumor antigen B7-H3 and identify tonic signaling, antigen-independent CAR activation, as a key determinant of therapeutic performance. B7-H3 CAR-T cells with minimal tonic signaling show superior tumor killing, persistence, and resistance to exhaustion in patient-derived DIPG models. Integrative single-cell and multi-omic profiling identifies a tonic signaling–associated gene signature that consistently outperforms conventional exhaustion or stemness markers in predicting CAR-T efficacy across multiple independent clinical trial datasets, including DIPG/DMG and other tumor types. Thus, our findings establish a mechanistic and predictive framework to guide CAR design and improve clinical outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE305987 | GEO | 2025/12/04

REPOSITORIES: GEO

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Tonic Signaling Shaped by Epitope Targeting Governs CAR-T Cell Fitness and Antitumor Activity in Diffuse Midline Glioma [CUT&Tag]

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