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Head and neck squamous cell carcinoma (HNSC) is a common and fatal tumor with a bleak prognosis, posing a significant threat to human health. N6-methyladenosine (m6A) modification regulates tumor progression by modulating gene expression post-transcriptionally. Nevertheless, the specific function of m6A-modified tumor drivers in HNSC remains largely uncharted. In this study, we revealed the pro-oncogenic role of m6A-regulated NTMT1 in HNSC through comprehensive pan-cancer analysis and experimental validation. By scrutinizing the prognostic and expression profiles of NTMT1 across over 30 cancer types, we observed a significant association between NTMT1 and patient overall survival in ACC, HNSC, LAML, LGG, KIRC, and STAD. Moreover, we find a close correlation between NTMT1 and disease-free survival in ACC, HNSC, LUSC, UVM, KIRC, and STAD. NTMT1 exhibited dysregulation in 15 cancers, including CESC, CHOL, COAD, DLBC, GBM, HNSC, LGG, LIHC, PAAD, READ, SKCM, THYM, UCS, LAML, and TGCT. Integrated data underscored the critical involvement of NTMT1 in HNSC. Furthermore, the expression of NTMT1 was closely associated with tumor stage and immune infiltration in HNSC. Functionally, NTMT1 deficiency was demonstrated to significantly impede cell proliferation and cell-cycle progression in HNSC. Mechanistically, METTL3 was elucidated to mediate the epigenetic upregulation of NTMT1 in HNSC in an m6A-dependent manner, and the overexpression of METTL3 was shown to alleviate the inhibitory impact of downregulated NTMT1 on HNSC proliferation. In conclusion, our findings enhance our understanding of NTMT1's role across various cancer types and offer a rationale for clinically targeting NTMT1 as a therapeutic approach for HNSC., (© 2023 Wiley Periodicals LLC.)