Reciprocal regulation between ferroptosis and STING-type I interferon pathway suppresses head and neck squamous cell carcinoma growth through dendritic cell maturation.

Head and neck squamous cell carcinoma (HNSCC) presents a serious clinical challenge mainly due to its resistance to conventional therapies and its complex, immunosuppressive tumor microenvironment. While recent studies have identified ferroptosis as a new therapeutic option, its impact on the immune microenvironment in HNSCC remains controversial, which may hinder its translational application. Although the role of the stimulator of interferon genes (STING)-type I interferon (IFN-I) pathway in antitumor immune responses has been widely investigated, its relationship with ferroptosis in HNSCC has not been fully explored. In this study, we discovered that ferroptosis in HNSCC inhibited tumor growth, activated STING-IFN-I pathway and subsequently improved recruitment and maturation of dendritic cells. We further demonstrated that IFN-I could enhance ferroptosis by inhibiting xCT-glutathione peroxidase 4 (GPX4) antioxidant system. To harness this positive feedback loop, we treated HNSCC tumors with both ferroptosis inducer and STING agonist, resulting in significant tumor suppression, elevated ferroptosis levels and enhanced dendritic cell infiltration. Overall, our findings reveal a mutually regulatory relationship between ferroptosis and the intrinsic STING-IFN-I pathway, providing novel insights into immune-mediated tumor suppression and suggesting its potential as therapeutic approach in HNSCC.