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While patients who respond to checkpoint inhibitors tend to develop a durable response, &lt;15% of patients with HNSCC respond to immune checkpoint inhibitors, underscoring the critical need to alleviate cancer resistance to immunotherapy. Major advances have been made to elucidate the intrinsic and adaptive resistance mechanisms to immunotherapy. Central genomic events in HNSCC have been found to possess previously unknown roles in suppressing immune sensing. Such inhibitory function affects both the innate and adaptive arms of tumor-specific immunity. While checkpoint blockade effectively reinvigorates adaptive T-cell responses, additional targeting of the oncogenic inhibitors of innate immune sensing likely informs a novel and potent strategy for immune priming. This review discusses the recent advances on the identification of key HNSCC oncogenes that impair antitumor immunity and emerging immune-priming approaches that sensitize poorly immunogenic HNSCCs to checkpoint blockade. These approaches include but are not limited to cancer vaccine systems utilizing novel type I interferon agonists as immune adjuvants, radiation, DNA damage-inducing agents, and metabolic reprogramming. The goal of these multipronged approaches is to expand tumor-specific effector T-cells, break checkpoint receptor-mediated tolerance, and metabolically support sustained T-cell activation. The translation of therapeutics that reverses oncogenic inhibition of immune sensing requires thorough characterization of the HNSCC regulators of innate immune sensors, development of additional immunocompetent HNSCC mouse models, as well as engineering of more robust immune adjuvant delivery systems. Built on the success of checkpoint blockade, validation of novel immune-priming approaches holds key promises to expand the pool of responders to immunotherapy.<\/jats:p>","DOI":"10.1177\/0022034519864112","type":"journal-article","created":{"date-parts":[[2019,7,24]],"date-time":"2019-07-24T20:07:06Z","timestamp":1563998826000},"page":"1073-1080","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":23,"title":["Head and Neck Cancer Immunotherapy beyond the Checkpoint Blockade"],"prefix":"10.1177","volume":"98","author":[{"given":"B.R.","family":"Heath","sequence":"first","affiliation":[{"name":"Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA"},{"name":"Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI, 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