Immunotherapy-based strategies (i.e. anti-programmed cell death protein-1 (anti-PD1) are highly suitable options for VA patients given the more favorable toxicity profile compared to chemotherapy strategies and the remarkable durable tumor responses that can be triggered. However, only a minority of patients derive benefit from single-agent immunotherapies and improvements are needed before routine use of anti-PD1 agents as first-line treatment. Therefore there remains a significant need to identify novel alternative immunotherapeutic strategies in order to improve survival outcomes for VA HNSCC patients. We propose that interleukin-1 (IL-1) ligands (e.g. IL-1α and/or IL-1β) may represent an effective immunotherapy in HNSCC patients. IL-1 signaling can activate a robust anti-tumor immune response via increased antigen presentation by dendritic cells (DCs), triggering of natural killer (NK) cell activity, and activation/proliferation of CD4+ and cytotoxic CD8+ T cells. This suggests that increasing levels of circulating IL-1 ligands may trigger anti-tumor immunity and enhance HNSCC tumor response to other therapeutic strategies that can induce anti-tumor responses such as radiotherapy and anti-PD1 therapy. Our preliminary data has shown unprecedented and durable T cell- dependent anti-tumor responses with a single intraperitoneal administration of an IL-1α polyanhydride nanoparticle (IL-1αNP) formulation to mice as a single agent. Additionally, in comparison to administration of recombinant IL-1α which elicited severe weight loss and toxicity, IL-1αNPs showed no obvious signs of toxicity. Based on this data we believe that IL-1α administration using nanoparticle delivery may represent a promising immunotherapeutic approach AND adjuvant to other agents approved for the treatment of HNSCC that trigger anti-tumor immune responses (e.g. radiotherapy and anti-PD1). We hypothesize that IL-1NPs will trigger an anti-tumor immune response and enhance HNSCC tumor response to radiotherapy and anti-PD1 therapy. Aim 1 will evaluate the therapeutic efficacy and safety profile of IL-1NPs; Aim 2 will examine if IL-1NPs will enhance HNSCC tumor response to radiotherapy; and Aim 3 will examine if IL-1NPs will enhance HNSCC tumor response to anti-PD1 immunotherapy. If successful, IL-1NP delivery would represent a promising immunotherapeutic approach for VA HNSCC patients and we are hopeful that this work will lead to the clinical evaluation of novel combination immunotherapy strategies that include IL-1NP delivery.