As STAT3 mutations in HNSCC, leading to gain-of-function, have not been described, activation of STAT3 is presumably the result of enhanced signaling through its positive regulators (cytokines, growth factors and non-receptor TKs), or decreased signaling through its negative regulators (protein tyrosine phosphatase receptors) [36]. This evidence concerns the gene STAT3 and head and neck squamous cell carcinoma.