Immunosuppressive Tumor Microenvironment and Therapeutic Landscape of Diffuse Intrinsic Pontine Glioma

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive and fatal pediatric brainstem tumor, characterized by rapid progression and extremely poor prognosis. Its infiltrative growth within the pons, combined with the critical function and inaccessibility of the brainstem, makes surgical resection different and significantly limits therapeutic options. Moreover, the molecular and cellular heterogeneity of DIPG complicates therapeutic development, and despite decades of research, the current standard of care remains limited to palliative radiotherapy. In recent years, tumor immunology in DIPG has gained attention, as its immunosuppressive microenvironment, resulting in an immunologically 'cold' tumor, presents both a challenge and an opportunity for advancing immunotherapeutic strategies. In this review, we focus on outlining what is known about the developmental biology, pathological hallmarks, and immunosuppressive tumor microenvironment of DIPG, including immune infiltration and function of both immunosuppressive cells and effector NK and T cells. We also summarize recent advances in the therapeutic landscape of DIPG, including targeted therapies (epigenetic modulators, receptor tyrosine kinase inhibitors, cell cycle and DNA damage response inhibitors, metabolic immune modulators), immunotherapies (adoptive cell therapy, immune checkpoint inhibitors, vaccine therapy and oncolytic virotherapy), and novel delivery approaches currently under preclinical and clinical investigation. Emerging trends highlight the potential of combination therapies to enhance treatment efficacy. A deeper understanding of DIPG biology and tumor microenvironment is critical for advancing more effective therapies for this aggressive disease among these vulnerable populations.