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
  • 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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