Chapter 6 │ Page 209 likely to benefit from NTP. To date, unlike therapies such as ICI (against the PD-(L)1 axis), where PD-L1 combined positive score (CPS) of the tumor is used as a biomarker to decide treatment course and patients’ response [73-75], there are no biomarkers or parameters available to foresee cancer cell vulnerability to NTP. Current applications rely majorly on the concept of the disturbed redox balance in cancer cells compared to normal cells. However, cancer-specific features, such as altered membrane properties, including di erences in cholesterol content and membrane fluidity, may influence NTP susceptibility [76, 77]. These features are underexplored and represent a completely novel research domain. If future work could uncover such predictive parameters, this would be a major step toward patient stratification and personalized application of plasma-based therapies. In parallel with the prominent goal of the plasma-oncology field to establish the clinical translation of NTP, several fundamental and mechanistic questions about its e ects on intertumoral and tumor–immune interactions remain unanswered. We shed light on the impact of NTP-induced oxidation on a broad range of functionregulating surface proteins and immune checkpoints for NK cells (Chapter 4), but a deeper investigation into its broader immunological impact is necessary. Despite our current research e orts, little is known about NTP’s influence on key immune checkpoints such as the PD-1/PD-L1 axis[13, 54], CTLA-4, and emerging targets like TIGIT, TIM-3, and LAG-3. Understanding how NTP modulates these inhibitory pathways could provide crucial insights into its potential to complement ICI therapies. Additionally, while most research is focused on tumor cell responses, the direct e ect of NTP on immune cells themselves is largely unexplored. Investigating how NTP influences crucial components of the TME, including DCs, macrophages, NK and T cells will be essential to fully comprehend the immunomodulatory characteristics. Improving our understanding of the e ect on both innate and
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