Abstract Integrating multimodal data can uncover causal features hidden in single-modality analyses, offering a comprehensive understanding of disease complexity. This study introduces a multimodal fusion subtyping (MOFS) framework that integrates radiological, pathological, genomic, transcriptomic, and proteomic data from 122 patients with IDH-wildtype adult glioma, identifying three subtypes: MOFS1 (proneural) with favorable prognosis, elevated neurodevelopmental activity, and abundant neurocyte infiltration; MOFS2 (proliferative) with the worst prognosis, superior proliferative activity, and genome instability; MOFS3 (TME-rich) with intermediate prognosis, abundant immune and stromal components, and sensitive to anti-PD-1 immunotherapy. STRAP emerges as a prognostic biomarker and potential therapeutic target for MOFS2, associated with its proliferative phenotype. Stromal infiltration in MOFS3 serves as a crucial prognostic indicator, allowing for further prognostic stratification. Additionally, we develop a deep neural network (DNN) classifier based on radiological features to further enhance the clinical translatability, providing a non-invasive tool for predicting MOFS subtypes. Overall, these findings highlight the potential of multimodal fusion in improving the classification, prognostic accuracy, and precision therapy of IDH-wildtype glioma, offering an avenue for personalized management.