Recently, immune checkpoint inhibitors (ICIs) entered the therapeutic spectrum of HNSCC and the potential biomarker value of the TP53 gene mutation, the most common genetic mutation in these cancers, associated with the accumulation of p53 in the malignant cell, is investigated in correlation with tumor mutation burden (TMB) and tumor neo-antigens (TNA), both for HNSCC primary tumor and for distant metastases. This evidence concerns the gene TP53 and cancer.