Redox heterogeneity in head and neck cancer: toward targeted therapies

Abstract

Head and neck squamous cell carcinoma (HNSCC) remains a persistent clinical challenge due to its aggressive nature, high degree of heterogeneity, and the debilitating side effects associated with current standard-of-care treatments. While it is well established that cancer cells operate under heightened levels of oxidative stress, the precise role of reactive oxygen species (ROS) and how to exploit them for HNSCC therapy has remained incompletely understood. To provide a broader understanding for personalized therapies, this doctoral dissertation investigates the complex redox homeostasis of HNSCC across diverse subtypes. Using a panel of cell lines and xenograft models, results revealed distinct redox signatures, highlighting the potential role of redox heterogeneity in shaping the response of HNSCC subtypes to oxidative stress based treatments. Following, two innovative, ROS-based therapeutic strategies, including non thermal plasma (NTP) and ROS-responsive nanocarrier (NC) systems, were evaluated to enhance tumor selectivity while minimizing systemic toxicity. To assess NTP, a novel liquid-submerged plasma-jet was developed, which significantly enhanced plasma-liquid interactions with phosphate buffered saline (PBS). This setup generated exceptionally high H2O2 concentrations while maintaining a stable pH. Plasma-treated PBS significantly reduced cancer cell viability and proliferation while sparing healthy keratinocytes. Notably, its efficacy exceeded that of reconstituted H2O2 and nitrite solutions, suggesting a synergistic effect targeting malignant cells. A complementary strategy utilized the tumor’s oxidative stress to trigger therapeutic release via dextran-based NCs with ROS-responsive thioketal linkages that degrade within the ROS-rich tumor microenvironment. These NCs demonstrated high biocompatibility and efficient cellular internalization. When loaded with chemotherapeutic payloads, they induced significantly higher cytotoxicity in cancer cells than non-responsive controls, concentrating drugs at the tumor site. In summary, this dissertation transitions from fundamental redox characterization to the development of targeted therapeutic strategies for HNSCC. Deciphering HNSCC redox signatures provides a framework for identifying tumors most susceptible to oxidative interventions. This work validates the potential of exploiting redox homeostasis, either through a direct pro-oxidant attack or a targeted delivery system, as a promising strategy that aims to improve therapeutic efficacy while reducing treatment related morbidity in HNSCC.