Chapter 6 │ Page 203 1. GENERAL DISCUSSION AND PROJECT POSITIONING The patient’s own immune system remains one of the most powerful defense mechanisms against cancer. Therefore, immune-stimulating therapies, including immune checkpoint inhibition, have become a major pillar in modern oncology. Unfortunately, even these rewarded agents still face significant hurdles, limiting their full potential [1-3]. This is most strongly exemplified in solid tumors, in which a hostile tumor microenvironment (TME) needs to be taken into account, a key factor that makes them far more resistant to ICI therapy compared to hematological malignancies [4-7]. While cancer therapy is increasingly shifting towards a personalized and targeted approach to overcome this patient- and tumor-specific immunosuppressive landscape, broader strategies that can enhance the tumor’s baseline immunogenicity retain their value, as they could make cancer cells more responsive to these highly specific and often costly therapies. In this PhD dissertation, I aimed to investigate the broad oxidative stress-induced immunomodulatory capacity of non-thermal plasma (NTP) and approached this from several angles, including tumor immunogenicity in the light of adaptive immunity and modulation of cancer surface proteins linked to the innate immunity. This study also provides a strong rationale for the further exploration of NTP in various immunological aspects and applications, for head and neck cancer (HNSCC) and beyond. In the first part of my study (Chapter 2), I demonstrated the importance of rigorous experimental and model optimization before evaluating therapeutic e icacy. This was shown by the observation that fluorophore-induced phototoxicity significantly altered the redox homeostasis in cancer cells and increased treatment susceptibility. Fluorescent reporters and imaging, widely used in research without much consideration, can cause unexpected confounding e ects that may compromise experimental accuracy. As cancer models become increasingly
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