AbstractBackgroundH3K27Mmutated diffuse midline gliomas (DMGs) are extremely aggressive and the leading cause of cancer‐related deaths in pediatric brain tumors with 5‐year survival <1%. Radiotherapy is the only established adjuvant treatment ofH3K27MDMGs; however, the radio‐resistance is commonly observed.MethodsWe summarized current understandings of the molecular responses ofH3K27MDMGs to radiotherapy and provide crucial insights into current advances in radiosensitivity enhancement.ResultsIonizing radiation (IR) can mainly inhibit tumor cell growth by inducing DNA damage regulated by the cell cycle checkpoints and DNA damage repair (DDR) system. In H3K27M DMGs, the aberrant genetic and epigenetic changes, stemness genotype, and epithelial‐mesenchymal transition (EMT) disrupt the cell cycle checkpoints and DDR system by altering the associated regulatory signaling pathways, which leads to the development of radio‐resistance.ConclusionsThe advances in mechanisms of radio‐resistance inH3K27MDMGs promote the potential targets to enhance the sensitivity to radiotherapy.