The high mutational burden in HNSCC should theoretically enhance immunogenicity, but gene heterogeneity and clonal evolution lead to resistance in several ways: (1) Driver gene mutations: Mutations in tumor protein 53 (TP53), notch receptor 1 (NOTCH1), and related genes inhibit T-cell infiltration by activating the wingless-int (WNT)/β-catenin pathway[53]. Here, TP53 is linked to head and neck squamous cell carcinoma.