We read with great interest the article by Liu et al., titled ” Clinical validation of a tissue-agnostic genome-wide methylome enrichment molecular residual disease assay for head and neck malignancies”[1]. This study substantiates the potential utility of a tissue-independent genome-wide methylation MRD assay in patients with head and neck cancer, demonstrating high sensitivity in both HPV-positive and HPV-negative cohorts. In comparison to circulating tumor HPV DNA used exclusively for HPV-positive oropharyngeal cancer, the assay presented in this research offers a broader scope of application.