The article by Wilson et al., published in the February 2021 issue, reported the prognostic value of circulating tumor DNA (ctDNA) sequencing in head and neck squamous cell carcinoma (HNSCC), noting TP53 as the most altered and concordant gene in ctDNA and tDNA. This Letter to the Editor further considers the role of TP53 alteration in the prognosis prediction of immunotherapy in HNSCC.