PROJECT SUMMARY An almost universal symptom of head and neck squamous cell carcinoma (HNC) is cancer-related pain. Oral cavity and oropharyngeal cancers are even more painful than the rest of the head and neck anatomic sites. HNC-associated pain frequently develops resistance to morphine and few strategies are available for effective pain management after they develop resistance. In addition, the inevitable morphine dose escalation leads to constipation, nausea, sedation, dry mouth, and myoclonus, which substantially decrease the patient’s quality of life. Recent studies have also shown that morphine has undesirable immunosuppressive features. Through the support of the parent R01 award, we have found that type-I interferon signatures underpin the immunogenicity of HNC and made seminal contributions to the understanding of oncogenic suppression of type-I interferons by promoting the rapid turnover of an adaptor protein, stimulator of interferon genes (STING). In addition to the potential of STING agonists in reprograming the antigen-presenting cells to cross prime CD8+ cytotoxic T- lymphocytes more effectively, we recently uncovered an unexpected yet powerful function of STING agonists in promoting analgesia. Hosts that are deficient in the STING-type-I interferon pathway show significantly elevated nociceptor excitability. We have found that common driver oncogenes for HNC initiation suppress STING and lead to type-I interferon deprivation in the tumor microenvironment. In this supplement proposal, we will provide transformative evidence to leverage type-I interferons for the management of HNC-associated, morphine-resistant pain. To achieve this goal, we have generated novel and rigorous HNC models with high fidelity resemblance to human HNC mutational features. We will integrate comprehensive modeling, behavior studies, and single-cell technologies to identify non-opioid agents for HNC pain management.