Hanne Verswyvel

Chapter 3 │ Page 70 engagement, and have the potential to form the foundation for next-generation cancer therapies. Non-thermal plasma (NTP) has emerged as a promising modality in that regard. Besides demonstrated anti-tumor e icacy, this partially ionized gas leverages its unique reactive species (ROS)-based working mechanisms to induce ICD and trigger immunological surveillance[25, 26]. Unlike more traditional treatments, NTP o ers a highly targeted, localized approach that could potentially synergize with existing therapies, improving their response rates. Taking a deeper dive into the immunogenic capacities, our lab has identified the short-lived RONS generated in the NTP (e.g., hydroxyl radicals (•OH), nitric oxide (•NO), and ozone (O/O₃)), as key drivers of ICD induction in cancer cells[26]. These reactive species cause, besides the direct cytotoxic e ects, a cascade of molecular adaptations in response to the experienced endoplasmic reticulum (ER) stress, which is an appealing feature of cancer therapies[27, 28]. Cisplatin (CDDP) and other platinum-based agents have been shown to induce features of anti-tumor immunity when used at low doses or in combination with ER stressors, such as ICD inducers[29-31]. By exacerbating ER stress, NTP may further enhance the immunogenic potential of CDDP, promoting DAMP release, neoantigen exposure, and immune activation. Similarly, since ER stress is also linked to improved antigen presentation[32, 33], NTP could synergize with ICIs to overcome tumor immune evasion and amplify anti-tumor T-cell responses. Building upon these findings and indications, our study aimed to determine whether NTP could improve the e icacy of CDDP in the context of ICD and tumor immunogenicity. To this end, we investigated the impact of NTP-CDDP combination therapy on tumor kinetics and survival in advanced 3D in vitro tumor models. Our results demonstrated synergistic responses in 3D HNSCC spheroids, and a declined survival in the advanced patient-derived HNSCC organoid model

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