From initial complete response to recurrence: ENPP1 mutation drives cisplatin resistance through STING/NF-κB/IL-6 axis in hypopharyngeal squamous cell carcinoma

Background Induction chemotherapy proves critical in hypopharyngeal squamous cell carcinoma (HPSCC). However, the mechanisms of acquired resistance to induction chemotherapy have not been fully elucidated yet.Methods Nine patients with HPSCC who showed an initial response to IC followed by progression and had available paired paraffin-embedded tissue samples were retrospectively analysed. Whole exome sequencing and functional validation were performed in both in vivo and in vitro experiments using CRISPR-Cas9-mediated knockout and mutant variant transfection.Results 66.7% (6/9) of the patients acquired novel mutations during progression. Among the newly emerged variants, alterations in ENPP1, ALK, and ATP10B were notable for potential functional relevance. Specifically, ENPP1 mutations were present in 50% (3/6) of the cases with acquired alterations. Functional assays demonstrated that ENPP1 knockout suppressed malignant phenotypes in vitro, while overexpression of the mutant ENPP1 (c.2596 G > C, p.Glu866Gln) promoted cisplatin resistance, enhanced 2'3'-cGAMP hydrolysis, and increased tumorigenic capacity in xenograft models. Mechanistically, ENPP1 mutation was associated with sustained activation of STING, accompanied by enchanced NF-κB signaling and elevated IL-6 production, ultimately promoting tumor cell survival and cisplatin resistance.Conclusion Our study identifies ENPP1 mutation as one of the key genetic drivers of recurrence, mediating both chemotherapy resistance and immunomodulation.