Hanne Verswyvel

Chapter 1 │ Page 15 Lastly, another promising, more global approach to improve immunotherapy e icacy is to enhance the immunogenicity of dying cancer cells (Figure 1) [47]. Conventional therapies, like chemotherapy and radiation, often induce immunological silent (apoptotic) cell death, especially in clinical regimes, which attenuates a strong anti-tumor response [48-50]. In contrast, immunogenic cell death (ICD) is a specialized form of regulated cell death that strongly stimulates the immune system by the release of damage-associated molecular patterns (DAMPs) and tumor antigens, leading to DC activation and T-cell priming [51]. If ICD induction could be optimized and strategically leveraged, it could amplify immune responses and improve the e icacy of ICIs and other immunotherapies. 1.4. Mechanisms Behind ICD: The role of Cellular Stress ICD is characterized by the presentation and release of numerous DAMPs, liberated in a controlled and timely manner [51, 52]. These immune-stimulating signalling molecules provide, together with novel tumor antigens, a kick-start to the front end of the cancer immunity cycle [51-53]. This process is typically induced by severe cellular stress, particularly oxidative stress and endoplasmic reticulum (ER) stress, often after treatment application [54]. Malignant growth and reactive oxygen species (ROS) have an intricate relationship, governed by a delicate balance between ROS generation and scavenging [55]. Cancer development and progression thrives under moderate elevations in ROS levels, allowing tumor cells to adapt and maintain a survival benefit via increased cellular metabolism and simultaneously adapted antioxidant system [55, 56]. In contrast, excess levels of ROS cause damage to a spectrum of intracellular structures (e.g., DNA, proteins, and lipids), which can cause cell death [56, 57]. Hence, this ROS adaptation of cancer cells compared to normal cells makes them intrinsically more vulnerable to external stimuli that further increase species production, pushing them over the tolerable threshold and leading to oxidative

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