Head and neck cancers (HNC) rank as the seventh most common malignancy worldwide, contributing significantly to cancer-related mortality. In 2022, more than 940.000 cases of HNC were reported and more than 480.000 deaths were recorded. In locally advanced stages (III and non-metastatic IV), radiochemotherapy is the standard treatment, administered either alone or as an adjuvant therapy following surgery. Despite advances in radiotherapy, HNC remain challenging due to the complexity of the anatomical region. In this context, iron oxide nanoparticles (IONPs) have been explored as potential radiosensitizers for HNC treatment, aiming to enhance radiotherapy efficacy while minimizing damage to surrounding healthy tissues. These nanoparticles are hypothesized to amplify cancer cell radiosensitivity by increasing reactive oxygen species (ROS) production and decreasing antioxidant defences. Furthermore, erastin, a known ferroptosis inducer, has been investigated in combination with IONPs to enhance the antitumor effects through oxidative stress generation.

In this study, IONPs coated with 3-(triethoxysilyl)propyl succinic anhydride (TEPSA) were used. Experiments using radiotherapy were performed using a 6 MeV beam. Clonogenic assays were conducted to assess the impact of IONPs on cell survival following exposure to various doses of radiation (2-8 Gy) and pre-treatment or not with nanoparticles. ROS generation, glutathione depletion, and thioredoxin reductase (TrxR) enzyme activity were measured to evaluate oxidative stress dynamics. Additionnaly, the effects of erastin were also evaluated alone and in combination with IONPs regarding cell viability, ROS production, and ferroptosis induction.

Results indicate that IONPs alone do not significantly reduce cell viability or enhance ROS production, though they are efficiently internalized across all tested HNC cell lines. The radiosensitizing effects of IONPs appear to be variable depending on the cell line and experimental conditions, and their overall impact remains insufficient. Interestingly, the combination of IONPs with erastin—at doses that are non-toxic when used separately—induces a marked decrease in cell viability and a concomitant reduction in ROS levels, suggesting a potential ferroptotic mechanism.

These findings highlight the promising role of IONPs and erastin in HNC treatment. Further investigations integrating radiotherapy are necessary to confirm their radiosensitizing potential and to elucidate the underlying molecular pathways, particularly ferroptosis induction.