Vinburnine Sensitizes Radiotherapy Efficacy in Nasopharyngeal Carcinoma by Triggering Pyroptosis and Immune Responses via Activation of EDAR‐NFκB Pathway

Abstract Radiotherapy combined with chemotherapy is the traditional treatment for nasopharyngeal carcinoma (NPC); however, the side effects of these therapies restrict their clinical application; therefore, identifying appropriate alternative chemotherapy agents is a critical clinical challenge. In this study, an approved drug library is assessed and identified vinburnine as a promising alternative chemotherapy agent that sensitizes NPC to radiotherapy with lower toxicity than cisplatin. Mechanistically, vinburnine directly interacts with ectodysplasin A receptor (EDAR), a member of the Tumor Necrosis Factor (TNF) receptor superfamily, which activates the radiotherapy‐induced Nuclear Factor Kappa B (NFκB) signaling pathway. As a consequence, vinburnine enhances radiotherapy‐induces apoptosis in NPC cells, promotes Gasdermin E (GSDME)‐mediated pyroptosis, and increases the secretion of chemokine (C‐C motif) ligand 5(CCL5) and C‐X3‐C Motif Chemokine Ligand 1 (CX3CL1), which promotes and strengthens T‐cell toxicity against NPC cells. Furthermore, it is found that EDAR expression is significantly greater in patients with nonrecurrent NPC than in those with recurrent disease and that EDAR expression is positively correlated with CD8 ⁺ T‐cell infiltration; thus, it may be a potential biomarker for NPC prognosis. Overall, the study revealed that vinburnine is a novel chemotherapeutic agent that increases the sensitivity of NPC to radiotherapy and revealed a novel mechanism by which vinburnine and radiotherapy collaboratively modulate the EDAR‐NFκB‐apoptosis/pyroptosis‐CCL5/CX3CL1 signaling pathway, which provides a promising therapeutic strategy for NPC.