Our results uncover the previously unrecognized findings that MUC1-C–induced chronic activation of the STAT1 inflammatory pathway in HNSCC cells regulates the lineage-dictating ∆Np63 and SOX2 genes, which are amplified in HNSCCs and contribute to HNSCC pathogenesis (Fig. 7D; refs. 8, 69). Here, STAT1 is linked to head and neck squamous cell carcinoma.