ECM-based molecular subtypes define prognostic, EMT status, and therapeutic diversity in IDH-mutant gliomas.

IDH-mutant gliomas show prognostic heterogeneity despite favorable overall outcomes, necessitating refined molecular classification. While the extracellular matrix (ECM) critically regulates tumor progression, immunity, and EMT, its prognostic significance in IDH-mutant gliomas remains largely unexplored. Here, we employed unsupervised clustering of ECM-related genes across multiple glioma cohorts, identifying two distinct molecular subtypes: ECM1 and ECM2. ECM1 correlated with worse prognosis, characterized by heightened immune infiltration, elevated EMT activity, aggressive radiological features (peritumoral edema/necrosis), and enhanced proliferation, angiogenesis, stemness, and matrix remodeling capacities. A four-gene signature (CLCF1, COL11A1, CSPG5, and SULF1) robustly stratified patient risk in validation cohorts. Subtype-specific analyses revealed divergent metabolic pathways and predicted differential drug sensitivities, highlighting therapeutic opportunities. Our findings establish ECM-driven heterogeneity as a key determinant of IDH-mutant glioma behavior, offering a novel molecular taxonomy to guide precision oncology through targeted ECM-related biomarkers and therapies.