Diffuse Intrinsic Pontine Glioma (DIPG) and H3K27M-Altered Diffuse Midline Glioma: Molecular Diagnostics, Therapeutic Frontiers, and Clinical Trial Landscape in 2025
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem glioma that classically arises in the pons and is characterized by diffuse infiltration, lack of surgical resectability, and historically poor outcomes. Over the last decade, molecular profiling has reframed DIPG within the broader category of diffuse midline gliomas (DMG), notably those harboring histone H3 lysine 27 to methionine mutations (H3K27M). This oncohistone change defines a biologically distinct subset strongly associated with adverse prognosis and unique epigenetic dysregulation. Clinically, the disease presents with rapidly progressive cranial neuropathies, long tract signs, and cerebellar dysfunction. Conventional focal radiotherapy remains the mainstay of initial disease control, while multimodal strategies—including re-irradiation at progression, locoregional delivery, and experimental immunotherapies—are being actively evaluated. In 2025, early-phase studies report feasibility and immune activation with oncolytic viruses, GD2-directed CAR T cells, and convection-enhanced radioimmunotherapy, reflecting a maturing translational pipeline. Importantly, in August 2025 the FDA approved oral dordaviprone (MODEYSO) for H3 K27M–mutant diffuse midline glioma with progressive disease in patients 1 year of age and older, marking a significant regulatory milestone that is reshaping trial design and clinical pathways in this population. This review synthesizes evidence across diagnostic pathology, clinical trials, and emerging therapeutics. We emphasize validated biomarkers such as H3K27M immunohistochemistry (IHC), evolving locoregional strategies (e.g., convection-enhanced delivery), and immuno-oncology approaches (oncolytic adenoviruses expressing IL-12 and GD2-directed CAR T cells). We also summarize the active clinical trials landscape using registry data to guide clinicians in current options and near-term developments.