Chapter 6 │ Page 208 incorporated into standard treatment regimens [55-60]. However, low and variable response rates and resistance mechanisms remain major challenges across these cancers [1, 2, 61]. Given its potential to enhance antigen presentation and counteract tumor-induced immune suppression, NTP may provide a solution to overcome these hurdles and improve treatment e icacy. Beyond these established conditions, ICIs are actively investigated in clinical trials for additional malignancies, earlier disease stages, and novel combinations and immune checkpoint targets [62-65]. If NTP’s immunogenic properties can be demonstrated to be consistent and robust, it holds promise as a potent adjuvant therapy to enhance ICI e icacy across a wide range of solid tumors. Another promising avenue worth investigating is the strategic combination of NTP with other therapeutic strategies, foremost other ER stress-inducing therapies to target cancer cells' altered redox balance. As tumor cells already display a higher ROS status, a dual approach, by systemic administration of ER stress-inducing agents with highly localized ROS overload via NTP, could be e ective in selectively pushing cancer cells over their redox threshold. Beyond direct cytotoxic e ects, this strategy could also trigger multiple stress response pathways, such as the unfolded protein response (UPR), which is linked to immunogenic cell death (ICD) induction [66]. Therefore, leveraging both routes of application simultaneously may enhance tumor cell killing and stimulate anti-tumor immunity. Various stress-inducing agents are in the research or clinical pipeline (e.g., small molecules, targeted therapies and natural derivates), and the repurposing of existing drugs represents a promising strategy as well [67-72]. If we can shed light on this concept, we could expand the clinical potential of both components in the combination approach, maximizing or even synergizing their e ects. Besides identifying rational combination strategies, a key translational aspect is determining whether certain tumor characteristics could predict patients most
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