PROJECT SUMMARY Clinical success of immune checkpoint receptor (ICR) blockade stems from its efficacy in restoring the effector function of exhausted tumor-infiltrating lymphocytes. But an exclusive effector immune cell-targeted treatment is prone to failure in hypoimmunogenic cold tumors, which are featured by insufficient elicitation of tumor-specific T-cell immunity and resistance to immunogenic cytotoxicity. Indeed, about 80% of Oral, Head & Neck Squamous Cell Carcinoma (HNC) patients do not respond to ICR blockade. Conventional chemoradiotherapy and surgical management are associated with high morbidity, such as swallowing problems, dry mouth, fungal infection, dead bone of the jaw, disfigurement, and “lock-jaw”. Deescalating treatment results in disease progression. Thus, it is urgent to characterize the mechanisms underpinning HNC hypoimmunogenicity. Our preliminary study identifies type I interferon signaling in the tumor microenvironment as a key pathway modulating the plasticity of anti-tumor immune response. Type I interferon target genes promote antigen-presenting cell (APC) and effector cell trafficking to the tumor bed, and enhance APC cross- priming efficiency. To mitigate the negative impact of cold HNC upon immune activation, we engineered a nano-vaccine system that potently enhances type I interferon signaling and antigen delivery. Our prototype nano-vaccine leads to an over 12-fold expansion of tumor-specific T cells in the tumor microenvironment, and significantly reduces tumor burden. Informed by our results and in response to the FOA, the overarching hypothesis of the project is: type I interferon signaling is essential to maintain HNC immunogenicity, and our nano-vaccine sensitizes cold HNC to ICR blockade. To test this hypothesis, three aims are put in place: **(1) we will characterize the role of type I interferon signaling in modulating HNC immunogenicity; **(2) we will determine the mechanisms HNC cells employ to dampen type I interferon signaling and promote resistance to checkpoint blockade; **(3) we will optimize a type I interferon-inducing tumor-specific nano-vaccine system to break HNC immune tolerance. These goals are in precise alignment with the FOA. (1) We will elucidate the role of type I interferon signaling in modulating the plasticity of anti-tumor immunity. (2) We will develop a safe, biocompatible, highly immunogenic and effective nano-vaccine technology to precisely and predictably enrich tumor antigen-specific T-cell repertoire.