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Simple Summary  Squamous cell cancer of the head and neck is a common malignancy with poor prognosis. Despite the success of PD-L1 expression, the landscape of diagnostic, prognostic, and predictive biomarkers has delivered limited contributions to the clinic in the last decade. The dissection of the immunological landscape through investigation of the immune infiltrate, blood-based biomarkers, and genetic profiling has shown substantial scientific potential but all are yet to be validated. Further exploration is warranted though implementation of biomarkers. This should ideally be performed through prospective studies using standardized methods with harmonization of technical requirements. This review serves as a comprehensive overview for state-of-the-art knowledge and biomarkers in squamous cell cancer of the head and neck (SCCHN) that may prove their worth in future clinical practice.    Abstract  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 clinical contributions. The untangling of the immune infiltrate with the subtyping of tissue-associated tumor infiltrating lymphocytes, tumor-associated macrophages, and circulating blood-based biomarkers are an interesting avenue to be further explored and prospectively assessed. Although PD-L1 expression remains the most important response predictor for immune checkpoint inhibitors, several flaws impede proper assessment such as technical issues, different scoring protocol, and intra-, inter-, and temporal heterogeneity. In addition, the construction of an immune-related gene panel has been proposed as a prognostic and predictive stratification but lacks consensus. Recently, the role of microbioma have also been explored regarding its systemic and antitumor immunity. This review gives a comprehensive overview of the aforementioned topics in SCCHN. To this end, the integration of these clinically advantageous biomarkers via construction of an immunogram or nomogram could be an invaluable tool for SCCHN in future prospects.

Immuno-Oncological Biomarkers for Squamous Cell Cancer of the Head and Neck: Current State of the Art and Future Perspectives