Chapter 3 │ Page 102 from tongue lesions[72, 73], these results may further support the notion that HNSCC subregions exhibit distinct immunogenic and molecular characteristics. Considering the dual and multi-functional role of many of these signaling molecules[74-76], it also remains challenging to draw definitive conclusions about their immunological impact in this context. While some cytokines are described as pro-inflammatory and immune-stimulating, they have also been linked to poor survival, tumor progression, or even metastasis in HNSCC, complicating interpretation [71, 75, 77-79]. To further elucidate the functional immune consequences of these signaling patterns, it is crucial to assess whether NTP-CDDP treatment e ectively improves anti-tumor immunity. Based on the promising ICD signatures observed in primarily DAMP presentation, which stimulates the first steps (tumor cell killing and DAMP release) from the cancer-immunity cycle[15], a logical next step is to assess direct immune activation by performing co-culture experiments with dendritic cells (DCs). DCs are the first immunological responders in the cancer-immunity cycle, playing a critical role in antigen uptake, processing, and T-cell priming [15, 80]. Evaluation of DC antigen uptake, phagocytosis, and maturation would complement our previously established secretion data, and as these experiments are currently being finalized, they will serve as a bridge to the ultimate confirmation of immunogenicity in vivo. In that light, our final research step was to validate bona fide ICD induction by conducting the gold-standard vaccination assay[26, 39, 40], designed to demonstrate immunological protection against cancer cell rechallenge within a complete biological system, in here a syngeneic HNSCC mouse model. This approach allowed us to assess whether our novel NTP-CDDP combination could evoke an e ective anti-tumor immune response, a critical property of ICD-driven therapeutic strategies. Our findings provided compelling evidence of NTP-CDDP
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