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Reciprocal regulation between ferroptosis and STING-type I interferon pathway suppresses head and neck squamous cell
Mingyu Li1,2,3, Shufang Jin2,3,4, Hailong Ma5,6,7
1Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, No. 639, Zhizaoju Rd, Shanghai, 200011, China.
Abstract:
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.
Insights
Ferroptosis in head and neck cancer suppresses tumors by activating the STING-IFN-I pathway, enhancing dendritic cell maturation. Combining ferroptosis inducers with STING agonists offers a promising therapeutic strategy for HNSCC.
Area of Science:
- Oncology
- Immunology
- Cancer Therapy
Background:
- Head and neck squamous cell carcinoma (HNSCC) is challenging due to therapy resistance and an immunosuppressive tumor microenvironment.
- Ferroptosis is a potential therapeutic strategy, but its immune effects in HNSCC are unclear.
- The STING-type I interferon (IFN-I) pathway's role in anti-tumor immunity is known, but its link to ferroptosis in HNSCC requires further investigation.
Purpose of the Study:
- To investigate the relationship between ferroptosis and the STING-IFN-I pathway in HNSCC.
- To explore the impact of ferroptosis on the tumor immune microenvironment in HNSCC.
- To evaluate the therapeutic potential of combining ferroptosis induction with STING pathway activation in HNSCC.
Main Methods:
- Utilized HNSCC models to study ferroptosis induction and its effects on tumor growth.
- Assessed the activation of the STING-IFN-I pathway in response to ferroptosis.
- Investigated the influence of IFN-I on the ferroptosis-regulating xCT-glutathione peroxidase 4 (GPX4) system.
- Administered combined ferroptosis inducers and STING agonists to HNSCC tumors in vivo.
Main Results:
- Ferroptosis inhibited HNSCC tumor growth and activated the STING-IFN-I pathway.
- Ferroptosis enhanced the recruitment and maturation of dendritic cells.
- IFN-I was found to potentiate ferroptosis by downregulating the xCT-GPX4 antioxidant system.
- Combined treatment with ferroptosis inducers and STING agonists led to significant tumor suppression, increased ferroptosis, and improved dendritic cell infiltration.
Conclusions:
- A positive feedback loop exists between ferroptosis and the STING-IFN-I pathway in HNSCC.
- This interplay contributes to immune-mediated tumor suppression.
- Targeting this ferroptosis-STING-IFN-I axis presents a novel therapeutic avenue for HNSCC.
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