Abstract Head and neck squamous cell carcinoma (HNSCC) is an extremely aggressive disease with poor overall survival. Despite the success of immune checkpoint blockade (ICB), the current forms of immunotherapy benefit only less than 15% of HNSCC patients. Therefore, there exists a critical need for new strategies for achieving powerful immune responses. STING (stimulator of IFN genes) is considered one of the key immune regulators that could convert non-responders to responders. Given the critical role of the STING pathway in cancer immunity, many pharmaceutical companies are racing to establish their discovery pipelines for STING agonists. However, conventional STING agonists have major limitations. Most STING agonists in clinical trials now are administrated via intratumoral injection due to their poor pharmaceutical properties. This precludes their applicability for the treatment of metastatic cancer. Therefore, there is an urgent need to identify and develop new STING agonists that can eliminate advanced cancer in an effective and safe manner. Here, we propose to develop the next- generation STING agonist nanoparticles with potent anti-tumor efficacy, favorable pharmaceutical properties, and acceptable safety profiles. We will develop novel STING agonist-based therapeutics and evaluate their efficacy in advanced animal models and perform large animal toxicity studies.