Hanne Verswyvel

Chapter 1 │ Page 16 stress-induced cell death. Moreover, this ROS overload, particularly within the mitochondria and ER, activates the unfolded protein response (UPR), a key stress response pathway that plays a pivotal role in orchestrating ICD as ROS-induced damage intracellularly reaches irreversible levels [58]. This process regulates the tra icking of key DAMPs, such as calreticulin (CRT), to the surface of cancer cells dying in an immunogenic way, thereby ultimately alarming anti-tumor immunity [59]. While the concept is promising, a major challenge lies in developing treatment strategies that can e ectively induce multiple facets of ICD without increasing toxicity. This is particularly crucial for cancer patients with advanced-stage disease and comorbidities, who often have limited tolerance for highly aggressive therapies. In this context, this study investigated non-thermal plasma (NTP) as a promising therapeutic option combining anti-cancer e ects with good tolerability, while simultaneously o ering the potential to induce immunomodulatory responses. 1.5. Non-Thermal Plasma as Novel Anti-Cancer Strategy: Selectivity, Tolerability, and Clinical Potential Non-thermal plasma (NTP), an ionized gas that is considered as the fourth state of matter, is composed of (positively and negatively charged) ions, free electrons, neutral gas molecules, and a multitude of short-lived and persistent reactive oxygen and nitrogen species (ROS/RNS) [60-62]. Unlike thermal plasma devices, such as argon coagulators or plasma scalpels, which generate high temperatures, NTP remains close to room temperature (~21°C) [63, 64]. This appealing characteristic has paved the way for biomedical applications, and initial medical applications could be found in wound healing, decontamination, and dental care [65, 66]. However, in the last two decades, reports about NTP’s potent anti-cancer properties have emerged [64, 67], creating the novel plasma-oncology research field.

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