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<p>Glioblastoma (GBM) patients have dismal survival due to resistance to initial ionizing radiation therapy (RT). Clonal evolution analysis reveals no dominant RT-resistant clones, prompting a genome-wide CRISPR screen to identify radiosensitizing targets. The screening highlights DNA damage response genes, validating the effectiveness of our approach. N-acylneuraminate-9-phosphatase (NANP), a critical enzyme in the sialic acid synthetic pathway, is top-ranked in the screening and associated with patient outcomes. After radiation, NANP-deficient cells exhibit more DNA damage, G2/M arrest and apoptosis, and impaired DNA repair by favoring non-homologous end-joining over homologous recombination. Mechanistically, NANP influences NF-κB signaling and the mesenchymal state by modulating sialylation and internalization of tumor necrosis factor receptor 1 (TNFR1), thereby affecting RT sensitivity. Intracranial orthotopic xenograft experiments validate the function of NANP in vivo. Here, we identify NANP as a radiosensitizing target dependent on TNFR1 sialylation and mesenchymal shift, providing a basis for developing RT sensitizers for GBM.</p>

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NANP targeting radiosensitizes glioblastoma through TNFR1 sialylation-driven mesenchymal shift

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月18日

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  • Yingwen Ding,
  • Ze-Yan Zhang,
  • Ravesanker Ezhilarasan,
  • Aram S. Modrek,
  • Melanie Graciani,
  • Jerome Karp,
  • Graysen McManus,
  • Ananya Jambhale,
  • Erik P. Sulman

摘要

Glioblastoma (GBM) patients have dismal survival due to resistance to initial ionizing radiation therapy (RT). Clonal evolution analysis reveals no dominant RT-resistant clones, prompting a genome-wide CRISPR screen to identify radiosensitizing targets. The screening highlights DNA damage response genes, validating the effectiveness of our approach. N-acylneuraminate-9-phosphatase (NANP), a critical enzyme in the sialic acid synthetic pathway, is top-ranked in the screening and associated with patient outcomes. After radiation, NANP-deficient cells exhibit more DNA damage, G2/M arrest and apoptosis, and impaired DNA repair by favoring non-homologous end-joining over homologous recombination. Mechanistically, NANP influences NF-κB signaling and the mesenchymal state by modulating sialylation and internalization of tumor necrosis factor receptor 1 (TNFR1), thereby affecting RT sensitivity. Intracranial orthotopic xenograft experiments validate the function of NANP in vivo. Here, we identify NANP as a radiosensitizing target dependent on TNFR1 sialylation and mesenchymal shift, providing a basis for developing RT sensitizers for GBM.