Additional Documents │ Page 222 cell carcinoma (HNSCC) and many other tumor types. My findings reveal synergistic cytotoxic e ects of NTP-CDDP combination therapy, with significant damageassociated molecular pattern release and cytokine modulation, underlining the robustness of the immune-stimulatory capacity of NTP. Moreover, the gold standard in vivo vaccination assay confirmed that NTP-CDDP enhances anti-tumor immunity, leading to nearly 40% protection against tumor rechallenge in a syngeneic mouse model. Despite the growing body of evidence for NTP’s immunomodulatory potential, few studies have considered relevant combination with current standardof-care, a critical gap in the field preceding clinical introduction which was addressed here. While adaptive immunity remains a major focus in immunotherapy, innate immunity, particularly natural killer (NK) cells, play a crucial role in anti-cancer immunity. In research chapter 4, I explored NTP’s e ects on tumor-associated NK cell ligands, demonstrating that oxidative stress induced by NTP modulates key immune checkpoints. Several inhibitory ligands, including TIGIT-axis markers and checkpoint CD73, were immediately downregulated, while MICA/B molecules as potent activators of NK cells, were upregulated 24 hours post-treatment. These findings suggest that NTP not only induces direct tumor cytotoxicity but also remodels the tumor immune landscape at various levels, making it a promising immune-modulating therapy. As future perspectives of this work, several concrete directions can be envisioned: (i) NTP’s therapeutic potential could extend beyond HNSCC, serving as an adjuvant strategy to enhance immunogenicity in other malignancies, such as non-small cell lung cancer and triple negative breast cancer, where ICI therapy faces challenges with low and variable response rates; (ii) combining NTP with other endoplasmic reticulum stress-inducing therapies may provide a dual, systemic-local, approach to disbalance cancer’s redox homeostasis, pushing tumor cells over their oxidative
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