Enhancing antitumor immunotherapy in head and neck cancer via ferroptosis-immune cascade activation by Fe-Shikonin nanomedicine.

Immunotherapy for head and neck squamous cell carcinoma (HNSCC) remains limited, and ferroptosis has emerged as an attractive route to enhance tumor immunogenicity; however, efficient induction of ferroptosis in vivo while engaging adaptive immune responses remains challenging. Here, we report a Fe-Shikonin nanomedicine for HNSCC therapy that couples tumor microenvironment-responsive disassembly with ferroptosis-associated immune activation. In the glutathione-rich tumor milieu, Fe-Shikonin dissociates to release ferrous ions and activate Fenton reactions, thereby amplifying reactive oxygen species generation, lipid peroxidation, and GPX4 suppression, leading to pronounced ferroptosis. Ferroptosis-associated oxidative stress further elicits immunogenic cell death-related signals, promoting dendritic cell maturation in vitro and in vivo, and enhancing cytotoxic CD8⁺ T cell responses, with splenic CD8⁺ T cells increasing from 8.0% to 15.5%, as supported by flow cytometry and single-cell transcriptomic analysis. Collectively, our study shows that Fe-Shikonin can function as a therapeutic nanomedicine in HNSCC and provides evidence for a ferroptosis-coupled immune activation cascade, offering a strategy for coordinated tumor cell killing and immune modulation in this disease setting.