Head and neck cancer is a serious global health problem with a wide range of histology and differentiation in the oral cavity, pharynx, and larynx (Johnson et al., 2020) with an estimated 177,757 deaths in 2021 and an annual incidence of roughly 377,713 (Sung et al., 2021). Head and neck squamous cell carcinomas (HNSCC) account for approximately 90% of all cancer subtypes (Ghiani and Chiocca, 2022). HNSCC treatment is based on surgical removal of the lesion, radiotherapy (RT), and chemotherapy (CT). Treatment becomes more challenging in recurrent and advanced stages of the disease (Ferreira et al., 2012, Goerner et al., 2010).

Growing data supports that manipulating an individual's immune system may be beneficial in patients' overall survival (OS) or even cancer eradication (Darvin et al., 2018). Checkpoint inhibitors (CI) including anti-programmed cell death protein 1 (PD-1), its ligand (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) have encouraged researchers to pursue similar routes of success in HNSCC (Dietz et al., 2021, Forster and Devlin, 2018). Previous studies in other cancers have demonstrated a synergetic effect of CI with CT as the latest can induce DNA damage and increase innate immunity (Della Corte et al., 2020).

In the context of combined therapies, the knowledge of cancer's molecular biology has driven the search for new treatments (Bozec et al., 2009). These breakthroughs have resulted in the identification of novel selective inhibitory drugs, often known as molecular-targeted therapeutics (Bernier et al., 2009, Bozec et al., 2009, Du et al., 2014, Gold et al., 2009, Kundu and Nestor, 2012, Le Tourneau et al., 2017, Machiels et al., 2015, Parsel et al., 2016, Prince et al., 2010, Sano et al., 2010). Targeted therapies based on tyrosine kinase inhibitors (TKI) are now being investigated in HNSCC very actively, and for this reason, the purpose of this review is to overview the clinical research on the use of TKIs in HNSCC therapy alone and in combination with immune CI.

This review was based on PubMed, Embase/Scopus, and Google Scholar search without date restriction following for studies in English languages until October 2022, using the keywords "Head and Neck Squamous Cell Carcinoma" and "Tyrosine Kinase". We also supplemented with clinical trials available at https://clinicaltrials.gov/. A careful reading of the titles and abstracts was performed, excluding articles that did not meet the objective of the article. Furthermore, a second screening based on the complete reading of the manuscripts was made to select the clinical trials and studies that included CI as combinatorial therapy.