Emerging role of immune checkpoint inhibitors and predictive biomarkers in head and neck cancers.

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Head and neck cancers are a group of diverse and heterogeneous tumors, among which squamous cell carcinoma of the head and neck (SCCHN) is the most prevalent. Current treatment modalities have limited efficacy; therefore, new therapies are being actively developed and evaluated. The introduction of immune checkpoint inhibitors (ICIs) has led to a paradigm shift in the management of difficult-to-treat malignancies. In this review, we summarize recent advances in the development of immunotherapies, which are aimed at the functional restoration of the immune system to counteract immune-evasion strategies of cancer cells, and related biomarkers. Monotherapies with ICIs, which primarily target the programmed cell death-1 (PD-1) pathway, have shown promising results in clinical trials of patients with recurrent and metastatic SCCHN. Combinations of ICIs with conventional or virus therapies often have synergistic therapeutic effects, without increased toxicity. As only a small subset of patients respond to immunotherapy, biomarkers are essential for the prediction of treatment response and better selection of patients for ICIs. PD-1 ligand (PD-L1) expression is correlated with response but has several limitations as a predictive marker, as its expression is dynamic and heterogeneous, and the cut-off needs further confirmation. Therefore, tumor mutation burden, gene expression signatures, microsatellite instability, tumor-infiltrating lymphocytes, viral antigens, and the oral microbiota are being investigated as predictive biomarkers. Finally, we delineate other challenges and future prospects for improving patient outcomes, including the major challenge of identifying and validating predictive biomarkers that need to be addressed in future studies.