Despite current therapeutic advances, head and neck cancer (HNC) is associated with bad prognoses. Recently, the use of cold plasma was proven to kill a variety of cancer cells including HNC cells without affecting healthy cells. This selective anti-cancer effect was mainly due to the reactive oxygen and nitrogen species (RONS) present in plasma. To prevent the side effects of direct plasma radiations, indirect treatments, in which plasma-activated liquids (PALs) are injected in the tumor as an off-the-shelf therapy, are preferred. Nonetheless, PALs are promptly diffused in the body leading to non-durable effects and HNC recurrences. This project launches a novel strategy based on plasma-activated hydrogels (PAHs) as local carriers of plasma-induced RONS for a sustained diffusion and effect. A clinical-grade thermosensitive hydrogel is injected as a liquid in the tumor where it crosslinks at body temperature. As such, the non-crosslinked liquid will be first exposed to a novel submerged atmospheric pressure plasma jet allowing the generation of high RONS concentrations. Extensive optimization of the plasma parameters leading to optimal physicochemical properties of the PALs and PAHs will be performed and iteratively evaluated using novel HNC 2D and 3D cell cultures and different animal models for HNC. If successful, this interdisciplinary project may achieve a major breakthrough in the treatment of HNC and can be extrapolated to other cancer types in the future.