2. Academic Validation
  3. Ara-C suppresses H3 K27-altered spinal cord diffuse midline glioma growth and enhances immune checkpoint blockade sensitivity

Ara-C suppresses H3 K27-altered spinal cord diffuse midline glioma growth and enhances immune checkpoint blockade sensitivity

  • Sci Adv. 2025 Apr 18;11(16):eadu3956. doi: 10.1126/sciadv.adu3956.
Bo Pang 1 2,  Yilin Wu 1,  SongYuan An 1 2,  Yuzhou Chang 1 2,  Hao Yan 1 2,  Han Lin 1 2,  Zheng Zhao 1 3 4,  Fan Wu 1 3 4,  Qing Chang 1,  Wenqing Jia 2,  Tao Jiang 1 2 3 4,  Yongzhi Wang 1 2 3 4,  Ruichao Chai 1 3 4
Affiliations

Affiliations

  • 1 Department of Molecular Neuropathology, Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
  • 2 Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 3 Research Unit of Accurate Diagnosis, Treatment, and Translational Medicine of Brain Tumors, Chinese Academy of Medical Sciences, Beijing, China.
  • 4 Chinese Glioma Genome Atlas Network (CGGA) and Asian Glioma Genome Atlas Network (AGGA), Beijing, China.
PMID: 40238864 DOI: 10.1126/sciadv.adu3956
Abstract

H3 K27-altered spinal cord diffuse midline glioma (H3-SCDMG) poses therapeutic challenges. Analysis of 73 clinical samples revealed heightened proliferation in H3-SCDMG versus wild-type tumors, suggesting therapeutic vulnerabilities. Drug screening identified cytarabine (Ara-C) as highly effective in inhibiting proliferation in H3 K27M cell models, recently established patient-derived cells, and patient-derived xenograft models. Mechanistically, Ara-C can suppress tumor growth through DNA damage, cell-cycle arrest, and Apoptosis. An investigator-initiated clinical trial involving four patients showed benefits in three cases. In addition, a subset of cells exhibited senescence and senescence-associated secretory phenotype post-Ara-C treatment, accompanied by several immune checkpoint ligands' up-regulation and more immune cell infiltration. Combining Ara-C with dual Programmed cell death protein 1 (PD-1) and TIGIT blockade emerged as a promising strategy to disrupt immune evasion by senescent cells, enhancing antitumor responses. These findings highlight Ara-C's potential as a monotherapy and in synergy with immunotherapy for H3-SCDMG, offering potential strategies for clinical management.

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