{"title":"铁螯合剂诱导的假性缺氧激活肺癌肿瘤免疫反应。","authors":"Yusuke Hamada, Toshiaki Ohara, Yuehua Chen, Manato Terada, Yuze Wang, Hotaka Kawai, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa","doi":"10.1080/10715762.2025.2551030","DOIUrl":null,"url":null,"abstract":"<p><p>Hypoxia-inducible factor (HIF) signaling plays a critical role in immune cell function. Pseudohypoxia is characterized as iron-mediated stabilization of HIF-1α under normoxic conditions, which can be induced by iron chelators. This study explored whether iron chelators exert antitumor effects by enhancing tumor immune responses and elucidating the underlying mechanisms. The iron chelators Super-polyphenol 10 (SP10) and Deferoxamine (DFO) were used to create iron-deficient and pseudohypoxia conditions. Pseudohypoxia induced by iron chelators stimulates IL-2 secretion from T cells and from both human and murine nonsmall cell lung cancer (NSCLC) cell lines (A549, PC-3, and LLC). Administration of SP10 reduced tumor growth when LLC tumors were implanted in C57BL/6 mice; however, this was not observed in immunodeficient RAG1-deficient C57BL/6 mice. SP10 itself did not directly inhibit LLC cells proliferation <i>in vitro</i>, suggesting an activation of the tumor immune response. SP10 synergistically enhanced the efficacy of PD-1 antibody therapy in lung cancer by increasing the number of tumor-infiltrating lymphocytes (TILs). In conclusion, iron chelation-induced pseudohypoxia activates tumor immune responses by directly upregulating HIF-1α, augmenting T cell function, and inducing IL-2 secretion from T cells, and cancer cells, thereby amplifying the immune efficacy of the PD-1 antibody in lung cancer treatment.</p>","PeriodicalId":12411,"journal":{"name":"Free Radical Research","volume":" ","pages":"1-13"},"PeriodicalIF":2.9000,"publicationDate":"2025-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pseudohypoxia induced by iron chelator activates tumor immune response in lung cancer.\",\"authors\":\"Yusuke Hamada, Toshiaki Ohara, Yuehua Chen, Manato Terada, Yuze Wang, Hotaka Kawai, Masayoshi Fujisawa, Teizo Yoshimura, Akihiro Matsukawa\",\"doi\":\"10.1080/10715762.2025.2551030\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Hypoxia-inducible factor (HIF) signaling plays a critical role in immune cell function. Pseudohypoxia is characterized as iron-mediated stabilization of HIF-1α under normoxic conditions, which can be induced by iron chelators. This study explored whether iron chelators exert antitumor effects by enhancing tumor immune responses and elucidating the underlying mechanisms. The iron chelators Super-polyphenol 10 (SP10) and Deferoxamine (DFO) were used to create iron-deficient and pseudohypoxia conditions. Pseudohypoxia induced by iron chelators stimulates IL-2 secretion from T cells and from both human and murine nonsmall cell lung cancer (NSCLC) cell lines (A549, PC-3, and LLC). Administration of SP10 reduced tumor growth when LLC tumors were implanted in C57BL/6 mice; however, this was not observed in immunodeficient RAG1-deficient C57BL/6 mice. SP10 itself did not directly inhibit LLC cells proliferation <i>in vitro</i>, suggesting an activation of the tumor immune response. SP10 synergistically enhanced the efficacy of PD-1 antibody therapy in lung cancer by increasing the number of tumor-infiltrating lymphocytes (TILs). In conclusion, iron chelation-induced pseudohypoxia activates tumor immune responses by directly upregulating HIF-1α, augmenting T cell function, and inducing IL-2 secretion from T cells, and cancer cells, thereby amplifying the immune efficacy of the PD-1 antibody in lung cancer treatment.</p>\",\"PeriodicalId\":12411,\"journal\":{\"name\":\"Free Radical Research\",\"volume\":\" \",\"pages\":\"1-13\"},\"PeriodicalIF\":2.9000,\"publicationDate\":\"2025-08-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Free Radical Research\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1080/10715762.2025.2551030\",\"RegionNum\":3,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Free Radical Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1080/10715762.2025.2551030","RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Pseudohypoxia induced by iron chelator activates tumor immune response in lung cancer.
Hypoxia-inducible factor (HIF) signaling plays a critical role in immune cell function. Pseudohypoxia is characterized as iron-mediated stabilization of HIF-1α under normoxic conditions, which can be induced by iron chelators. This study explored whether iron chelators exert antitumor effects by enhancing tumor immune responses and elucidating the underlying mechanisms. The iron chelators Super-polyphenol 10 (SP10) and Deferoxamine (DFO) were used to create iron-deficient and pseudohypoxia conditions. Pseudohypoxia induced by iron chelators stimulates IL-2 secretion from T cells and from both human and murine nonsmall cell lung cancer (NSCLC) cell lines (A549, PC-3, and LLC). Administration of SP10 reduced tumor growth when LLC tumors were implanted in C57BL/6 mice; however, this was not observed in immunodeficient RAG1-deficient C57BL/6 mice. SP10 itself did not directly inhibit LLC cells proliferation in vitro, suggesting an activation of the tumor immune response. SP10 synergistically enhanced the efficacy of PD-1 antibody therapy in lung cancer by increasing the number of tumor-infiltrating lymphocytes (TILs). In conclusion, iron chelation-induced pseudohypoxia activates tumor immune responses by directly upregulating HIF-1α, augmenting T cell function, and inducing IL-2 secretion from T cells, and cancer cells, thereby amplifying the immune efficacy of the PD-1 antibody in lung cancer treatment.
期刊介绍:
Free Radical Research publishes high-quality research papers, hypotheses and reviews in free radicals and other reactive species in biological, clinical, environmental and other systems; redox signalling; antioxidants, including diet-derived antioxidants and other relevant aspects of human nutrition; and oxidative damage, mechanisms and measurement.