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The era of immune checkpoint inhibitors has altered the therapeutic landscape in squamous cell cancer of the head and neck (SCCHN). Our knowledge about the tumor microenvironment has fueled the research in SCCHN, leading to several well-known and less-known prognostic and predictive biomarkers. The clinical staging, p16/HPV status, and PD-L1 expression are currently the main tools for assessing the patients' diagnosis and prognosis. However, several novel biomarkers have been thoroughly investigated, some reaching actual significant clinic