HPV-positive HNSCC usually displays a more favorable clinical outcome than HPV-negative HNSCC, resulting in the adaptation in the eighth edition of the tumor–node–metastasis (TNM) staging to include p16INK4A immunostaining to indicate HPV status.2 Recently, two immune checkpoint inhibitors, pembrolizumab and nivolumab, have been approved by the Food and Drug Administration (FDA) for the treatment of recurrent or metastatic HNSCC (R/M-HNSCC), and pembrolizumab is a first-line therapy for unresectable tumors.7–9 However, the prognosis remains poor. This evidence concerns the gene CDKN2A and head and neck squamous cell carcinoma.