Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide, and advanced HNSCC patients often experience relapse or metastasis (R/M HNSCC) resulting in dismal prognoses. These patients receive immunotherapy (ICI) alone or in combination with platinum-based chemotherapeutics (PLAT) as first-line treatment. While these combination treatments have some clinical benefit, they are limited by low response rates and severe side effects in already weakened patients. To address this, I will investigate a novel combination strategy with non-thermal plasma (NTP). NTP, an ionised gas, is a localised therapy that induces immunogenic cancer cell death (ICD), which can activate the patient's anti-cancer immunity. To date, no adverse side effects have been reported with the clinical use of NTP. Therefore, we hypothesize that combining NTP with PLAT/ICI will be well-tolerated and improve clinical efficacy in R/M HNSCC. In this project, I will perform 3D in vitro experiments on cell lines and primary patient material, and two mouse models will be used to validate the safety and clinical efficacy of this combination strategy. The successful completion of my project will help integrate NTP into current first-line therapies of R/M HNSCC as a new combination strategy to improve treatment efficacy and quality of life for those patients. This study will also be a stepping stone towards a broader implementation of NTP technology in other cancer types.