Epigenetic modulation of immunotherapy and implications in head and neck cancer

Cancer progression is facilitated by distinct mechanisms developed by cancer cells to avoid immune recognition and clearance. The clinical application of immune checkpoint blockade (ICB), via monoclonal antibodies blocking PD-1/PD-L1 and CTLA4, has achieved promising durable therapeutic response in various cancer types, including recurrent and metastatic head and neck squamous cell carcinomas (HNSCC). HNSCC represents a rational target of ICB treatment given its relatively high mutation burden and the presence of immune infiltrates. However, the limited response rates and recent negative clinical trials data identify an urgent need for new strategies to overcome immunotherapy resistance. Preclinical studies have revealed an important contribution of epigenetic regulators in the anti-tumor immune response. Multiple components of the tumor and host immune system interaction are under epigenetic regulation, including the cancer cells themselves, cytotoxic T lymphocytes, regulatory T lymphocytes, natural killer cells, and tumor-associated macrophages. Epigenetic targeting drugs such as DNA methyltransferase inhibitors, histone deacetylase, and methyltransferase inhibitors have demonstrated the potential to reverse immune suppression in various cancer models. The aim of this review is to summarize recent preclinical studies focused on investigating the function of epigenetic modulation in the host immune and cancer cell interface. We also provide a perspective on combining epigenetic modulation and immunotherapy in the management of HNSCC to improve outcomes-an area of great interest in future clinical studies.