The survival rate of head and neck squamous cell carcinoma patients with the current standard of care therapy is suboptimal and is associated with long-term side effects. Novel therapeutics that will improve survival rates while minimizing treatment-related side effects are the focus of active investigation. Epigenetic modifications have been recognized as potential therapeutic targets in various cancer types, including head and neck cancer. This review summarizes the current knowledge on the function of important epigenetic modifiers in head and neck cancer, their clinical implications and discusses results of clinical trials evaluating epigenetic interventions in past and ongoing clinical trials as monotherapy or combination therapy with either chemotherapy, radiotherapy or immunotherapy. Understanding the function of epigenetic modifiers in both preclinical and clinical settings will provide insight into a more rational design of clinical trials using epigenetic interventions and the patient subgroups that may benefit from such interventions.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is associated with high mortality. The main reasons for treatment failure are a low rate of early diagnosis, high relapse rates, and distant metastasis with poor outcomes. These are largely due to a lack of diagnostic, prognostic, and predictive biomarkers in HNSCC. DNA methylation has been demonstrated to play an important role in the pathogenesis of HNSCC, and recent studies have also valued DNA methylation as a potential biomarker in HNSCC. This review summarizes the current knowledge on DNA methylation profiles in HPV-positive and HPV-negative HNSCC and how these may contribute to the pathogenesis of HNSCC. It also summarizes the potential value of DNA methylation as a biomarker in the diagnosis, prognosis, and prediction of the response to therapy. With the recent immunotherapy era in head and neck treatment, new strategies to improve immune responses by modulating TIMEs have been intensely investigated in early-phase trials. Therefore, this study additionally summarizes the role of DNA methylation in the regulation of TIMEs and potential predictive immunotherapy response biomarkers. Finally, this study reviews ongoing clinical trials using DNA methylation inhibitors in HNSCC.

In head and neck squamous cell carcinoma (HNSCC), anti-PD-1 inhibitors are approved for recurrent/metastatic (R/M) disease and anticipated to expand to other indications. The impact of p16 status and anatomical site on overall survival (OS) in immunotherapy-treated HNSCC patients remains unresolved. We performed a retrospective analysis of R/M HNSCC patients receiving anti-PD-1 immunotherapy at our academic medical center with an extensive community satellite network. Fifty-three R/M HNSCC patients were treated with anti-PD-1 immunotherapy and had a median OS of 6 months. Anatomical site was associated with distinct OS; oropharynx and larynx patients have superior OS compared to oral cavity patients. Analysis of the OPSCC subset showed p16+ status as a favorable, independent prognostic biomarker (HR 7.67 (1.23–47.8); p = 0.029). Further studies to assess the link between anatomical site, p16 status, and anti-PD-1 treatment outcomes in large cohorts of R/M HNSCC patients managed in real-world clinical practices and clinical trials should be prioritized.