Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. Patients have a median survival time of less than 20 months and an extremely poor prognosis. The current standard treatment strategy includes surgical resection, temozolomide chemotherapy, and radiotherapy. Among these, radiotherapy is the most effective first-line treatment for prolonging patient survival. However, nearly all patients eventually experience recurrence and death due to the development of radiotherapy resistance. This resistance is closely associated with a population of “glioblastoma stem cells (GSCs)” within the tumor that possess self-renewal capacity and strong resistance to radiotherapy. Finding ways to overcome this radiotherapy resistance has become a critical challenge for improving patient outcomes.

Recently, Researcher Zhang Zeyan from the School of Basic Medical Sciences, Nanchang University, in collaboration with researchers from New York University, Duke University, and other institutions, published a research article entitled “NANP targeting radiosensitizes glioblastoma through TNFR1 sialylation-driven mesenchymal shift” in Nature Communications. This study reveals, for the first time, that NANP, a key enzyme in the sialic acid biosynthesis pathway, regulates sialylation and endocytosis of tumor necrosis factor receptor 1 (TNFR1), thereby activating the NF-κB signaling pathway and driving the phenotypic transition of glioblastoma stem cells (GSCs) toward a mesenchymal (MES) phenotype. These findings identify NANP as a promising potential therapeutic target for enhancing radiosensitivity in glioblastoma.

Using patient-derived GSCs as an experimental model system, the researchers first employed single-cell DNA barcode lineage-tracing technology and found that, unlike resistance to targeted therapies, radiotherapy resistance does not significantly enrich for specific resistant subclones. This observation suggests that “global radiosensitization” represents a more feasible therapeutic strategy. The team further conducted genome-wide CRISPR screening and identified NANP, a key enzyme in the sialic acid biosynthesis pathway, as one of the most prominent previously unrecognized targets for radiosensitization. High expression of NANP is closely associated with tumor resistance to radiotherapy. Experimental results demonstrated that silencing NANP significantly enhanced radiation-induced DNA damage, G2/M phase arrest, and apoptosis in tumor cells, thereby increasing the sensitivity of GBM to radiotherapy. Mechanistically, the study revealed that NANP regulates the sialylation and endocytosis of TNFR1, leading to activation of the NF-κB signaling pathway and driving the transition of GSCs toward a mesenchymal (MES) phenotype, ultimately resulting in radiotherapy resistance in glioblastoma.

This study reveals the mechanism underlying radiotherapy resistance in glioblastoma and provides important theoretical foundations and potential therapeutic targets for the development of novel radiosensitizers.

Researcher Zhang Zeyan from the School of Basic Medical Sciences and Dr. Ding Yingwen are the co-first authors of this paper. Professor Erik P. Sulman, Acting Executive Director of the Duke Cancer Institute and Chair of the Department of Radiation Oncology, serves as the corresponding author. Nanchang University is listed as the first affiliated institution.