PROJECT SUMMARY. Conventional multi-modality therapy for Head and Neck Squamous Cell Carcinoma (HNSCC), such as surgery and chemoradiotherapy, can result in off-target effects and often fails to eradicate cancer, resulting in high locoregional and distant recurrence rates. The adverse tumor immune microenvironment (TIME) in HNSCC has been shown to: 1) impair tumor-infiltrating lymphocyte function, 2) decrease the production of effector cytokines, and 3) contain suppressive immunocytes. Thus, there is strong interest in developing strategies to mitigate the suppressive TIME and elicit a strong anti-tumor immune response. A successful immunotherapy approach should also boost immunological memory and thus reduce cancer recurrence. Most HNSCC patients treated with single-agent FDA-approved immunotherapies do not respond, in large part due to the immunosuppressive TIME. A drug delivery innovation that addresses immunotherapy's shortcomings while reducing side effects could significantly impact HNSCC treatment. To overcome these limitations, we propose a novel hydrogel-based platform for spatiotemporal control over the delivery of cytokines, specifically, lnterleukin-2 (IL-2), lnterleukin-12 (IL-12), and lnterleukin-15 (IL-15) to stimulate antitumor effector cells and suppress myeloid-derived suppressive cells (MDSCs). Our L-NIL functionalized multi-domain peptide hydrogel platform (SynerGel) can be injected intratumorally to deliver and release immunomodulators into the TIME locally. We hypothesize the combination of cytokines in our SynerGe/ platform will localize and extend the release of these immunomodulators intratumorally, stimulating anti-tumor effector immunocytes in synergy with the suppression of MDSCs. To investigate this hypothesis, we will evaluate SynerGe/ as an injectable, highly customizable cancer immunotherapy platform able to perform sustained delivery of multiple cytokines to the TIME (Aim 1) and identify specific immune mechanisms contributing to the efficacy of cytokine-releasing SynerGels in the HNSCC tumor microenvironment (Aim 2). We anticipate the combination of cytokines in SynerGel will have controlled release, suppress MDSCs, and stimulate anti-tumor effector immune cells for durable responses. This project offers a biomaterial-based approach to deliver immunotherapeutics to the suppressive TIME in HNSCC. Dr. Simon Young will serve as the primary mentor of the trainee with the co-mentorship of Dr. Mary Cindy Farach-Carson. During graduate degree training, the candidate will meet with mentors regularly, write first-author publications, and present research findings at conferences. This supplement will help the trainee develop scientific and communication skills, leadership qualities, and a deeper understanding of the tumor immune microenvironment in head and neck cancers, aligning with the candidate's goal of becoming an independent translational researcher.