Li Mingyu, Jin Shufang, Ma Hailong, Yang Xi, Zhang Zhiyuan
Department 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.
National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology. No. 639, Zhizaoju Rd, Shanghai, 200011, China.
Oncogene. 2025 Mar 31. doi: 10.1038/s41388-025-03368-2.
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.
头颈部鳞状细胞癌（HNSCC）是一项严峻的临床挑战，主要原因在于其对传统疗法具有抗性，且肿瘤微环境复杂并具有免疫抑制性。尽管近期研究已确定铁死亡是一种新的治疗选择，但其对HNSCC免疫微环境的影响仍存在争议，这可能会阻碍其转化应用。虽然干扰素基因刺激剂（STING）-I型干扰素（IFN-I）通路在抗肿瘤免疫反应中的作用已得到广泛研究，但其与HNSCC中铁死亡的关系尚未得到充分探索。在本研究中，我们发现HNSCC中的铁死亡抑制肿瘤生长，激活STING-IFN-I通路，随后改善树突状细胞的募集和成熟。我们进一步证明，IFN-I可通过抑制xCT-谷胱甘肽过氧化物酶4（GPX4）抗氧化系统来增强铁死亡。为利用这一正反馈回路，我们用铁死亡诱导剂和STING激动剂治疗HNSCC肿瘤，结果显著抑制肿瘤、提高铁死亡水平并增强树突状细胞浸润。总体而言，我们的研究结果揭示了铁死亡与内在STING-IFN-I通路之间的相互调节关系，为免疫介导的肿瘤抑制提供了新见解，并表明其在HNSCC中作为治疗方法的潜力。
