Deciphering the tumor microenvironment and role of immunotherapy in Diffuse Midline Glioma: a scoping review

Diffuse midline glioma, H3 K27-altered, formerly known as diffuse intrinsic pontine glioma, (DIPG/DMG) is the most aggressive form of pediatric brain malignancy, with <10% 2-year overall survival after standard of care. The limited success of traditional immune checkpoint inhibitors in pediatric high-grade gliomas, including DMG, has highlighted the urgent need to re-examine the tumor's intrinsic and microenvironmental barriers to immunotherapy. Advances in molecular and spatial profiling have revealed the profound intratumoral heterogeneity, lineage plasticity, and complex immunosuppressive tumor microenvironment characteristic of DMG, which are shaped by diverse myeloid populations, neuronal integration, and spatially distinct tumor niches. These insights are informing the development of non-traditional immunotherapeutic approaches, including alternative checkpoint blockade, chimeric antigen receptor T cells, and viro-immunotherapy strategies, which aim to overcome DMG's unique immune escape mechanisms. We also outline key translational challenges and future directions necessary to accelerate progress, including the refinement of preclinical models, optimization of CNS-specific immunotherapy delivery, and the integration of patient-derived data into streamlined, collaborative clinical trial platforms.