Chapter 3 │ Page 103 immunogenicity (Figure 11), including improved tumor kinetics and prolonged survival after combination therapy. In addition, mice receiving the strongest NTPCDDP treatment exhibited 37.5% protection against tumor rechallenge, which is particularly striking given the aggressive nature of HNSCC. To prevent confounding tumor development on the vaccination site, the viability of all prepared vaccines was rendered very low, through overnight incubation in PBS. However, this also highlights the critical observation that not all forms of cell death were capable of eliciting protective immunity. While all groups received a vaccine composed of non-viable (<10%) tumor cells, only the NTP-based groups demonstrated significant protection, emphasizing the importance of specific ICDdriven immune activation rather than any regular cell death. Looking at the future, the next step would be to evaluate treatment e icacy of our NTP-CDDP combination in mice with established tumors, assessing its impact on tumor kinetics and survival outcomes on an actively growing HNSCC tumor. Ideally, these studies should be performed in an orthotopic setting, as this would better recapitulate tumor microenvironment interactions, local immune suppression, and surrounding tissue penetration [81, 82]. In the long term, a triple combination strategy incorporating ICI could be explored, leveraging NTP’s ICDinducing potential to improve response rates to checkpoint blockade therapy. To conclude, this study demonstrated the potential of NTP-CDDP combination therapy as a promising strategy to enhance tumor immunogenicity and overcome current treatment limitations. While additional studies are needed to deepen our knowledge on the immune activation mechanisms and in vivo treatment e icacy, our findings provide a clear framework for rationally designed combination strategies integrating NTP into conventional HNSCC therapies. Given that R/M HNSCC patients are often in poor condition with limited treatment options, NTP’s highly-localized application[25, 83], favorable safety profile[83, 84], and
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