Abstract
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.
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Data availability
All RNA-seq data were deposited in the NCBI GEO repository under accession GSE274135. Raw data for the genome-wide CRISPR screen and clonal evolution analysis have been deposited in the NCBI Sequence Read Archive (SRA) repository under accession number PRJNA1432116 (https://www.ncbi.nlm.nih.gov/sra). Other data that support the findings of this research are available within the paper and its Supplementary Information. Source data are provided with this paper.
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Acknowledgements
We thank Dr. Michael Pacold at NYU Langone Health for helpful discussions. We thank the NYU Langone Health’s Cytometry and Cell Sorting Laboratory for cytometry support; Experimental Pathology Research Laboratory for support on IHC experiment; Microscopy Laboratory for microscope imaging support and Preclinical Imaging Laboratory for small animal imaging support. These cores are all partially supported by the Cancer Center Support Grant P30CA016087 at NYU Langone’s Laura and Isaac Perlmutter Cancer Center. The Preclinical Imaging Laboratory is also partially supported by NIBIB Biomedical Technology Resource Center Grant NIH P41 EB017183. This work is supported by R01CA282756 (Y.D., Z.-Y.Z., and E.P.S.). This project was also supported by a grant from the NYU Technology Opportunities & Ventures Therapeutics Alliances Fund (Y.D., Z.-Y.Z.).
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E.P.S., Z.-Y.Z., and Y.D. conceived and designed the study; Y.D. and Z.-Y.Z. designed, performed, and analyzed most experiments; Z.-Y.Z., R.E., and M.G. performed in vivo study. G.M. and A.J. provided help with the experiments during revision. A.M., J.K. provided critical suggestions; R.E. did administration and management. Y.D., Z.-Y.Z., and E.P.S. wrote the manuscript. All authors have reviewed and revised the manuscript.
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Ding, Y., Zhang, ZY., Ezhilarasan, R. et al. NANP targeting radiosensitizes glioblastoma through TNFR1 sialylation-driven mesenchymal shift. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70853-x
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DOI: https://doi.org/10.1038/s41467-026-70853-x
