Diffuse midline glioma, H3K27-altered (DMG) is an oncohistone-driven malignancy. Effective treatment guideline is absent and remains to be established. Meanwhile, high grade glioma patients with leptomeningeal metastasis (LM) have an extremely poor median overall survival of 1.6–3.8 months. We report a patient of recurrent spinal cord DMG with LM who survived for 20 months with extraordinary tumor regression by treatment of epigenetic agent-based immunotherapy. Mass spectrometric analysis was performed to profile the whole proteome of cerebrospinal fluid across five time points during the treatment. We further achieved significant clinical responses in 3 more DMG patients. Our observations refreshed the paradigm that epigenetic therapy may contribute to reinvigorate the immunotherapeutic efficacy in immune “cold” gliomas. This could be leveraged to develop treatment strategies in the larger context of malignancies with epigenetic dysregulation.