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Simple Summary  H3K27M-mutant diffuse midline glioma is a rare childhood cancer originating in midline brain structures. The H3K27M mutation substitutes an amino acid on histone H3 that promotes gene expression and tumor growth. This cancer has a dismal prognosis and requires new and better treatment approaches. This review discusses controversies regarding tumor biopsy and summarizes molecular tumor characteristics that are therapeutic targets. We describe preclinical studies and clinical trials utilizing immunotherapy, radiation, and chemotherapy against this cancer.Abstract  H3K27M-mutant diffuse midline gliomas (DMGs) are rare childhood central nervous system tumors that carry a dismal prognosis. Thus, innovative treatment approaches are greatly needed to improve clinical outcomes for these patients. Here, we discuss current trends in research of H3K27M-mutant diffuse midline glioma. This review highlights new developments of molecular pathophysiology for these tumors, as they relate to epigenetics and therapeutic targeting. We focus our discussion on combinatorial therapies addressing the inherent complexity of treating H3K27M-mutant diffuse midline gliomas and incorporating recent advances in immunotherapy, molecular biology, genetics, radiation, and stereotaxic surgical diagnostics.

New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma