In addition, the present review discusses the most updated understanding of the role of DNA methylation in the tumor immune microenvironment (TIME) of HNSCC and its role as a potential biomarker for the prediction of the response to immunotherapy, such as PD1 inhibitors or CTLA-4 (cytotoxic T-lymphocyte associated protein 4) immune checkpoint inhibitors. Here, CTLA4 is linked to head and neck squamous cell carcinoma.