Diffuse Intrinsic Pontine Glioma in the Era of H3 K27-Altered Diffuse Midline Glioma

Diffuse intrinsic pontine glioma (DIPG), most commonly corresponding pathologically to diffuse midline glioma (DMG), H3 K27-altered, remains an overwhelmingly lethal pediatric brainstem malignancy, with median overall survival of approximately 11 months. We critically synthesized evidence identified through a structured search to December 31, 2025, supplemented by targeted updates of regulatory documents, clinical-trial records, and pivotal or practice-relevant publications through July 2026. We summarize epidemiology and the clinico-radiographic syndrome; examine the transition toward integrated molecular classification supported by stereotactic biopsy, with liquid biopsy emerging as a complementary tool; and distill core biology centered on PRC2 inhibition, loss of H3K27 trimethylation, developmental cell states, neuron-glioma interactions, and recurrent co-alterations involving TP53/PPM1D, ACVR1, PDGFRA, and PI3K/MAPK pathways. Radiotherapy remains the only modality with reproducible, albeit transient, clinical benefit; evidence supports hypofractionation in selected patients and reirradiation for carefully selected patients at recurrence. We appraise why cytotoxic chemotherapy and most targeted or epigenetic approaches have failed to deliver reproducible benefit, while highlighting early signals from CAR T-cell therapy, neoantigen vaccination, oncolytic virotherapy, and locoregional or ultrasound-enabled delivery. We also examine dordaviprone, the first systemic therapy to receive FDA accelerated approval for H3 K27M-mutant DMG with progressive disease following prior therapy, while emphasizing that the regulatory efficacy population excluded DIPG and therefore does not establish efficacy in classic pediatric pontine disease. Trial design must also explicitly separate anatomic phenotype from molecular taxonomy. Priorities include molecularly stratified enrollment, pharmacokinetically verified brainstem exposure, rational combinations, and endpoints integrating survival, neurologic function, and quality of life.