Tito A Sandoval, Camilla Salvagno, Chang-Suk Chae, Deepika Awasthi, Paolo Giovanelli, Matias Marin Falco, Sung-Min Hwang, Eli Teran-Cabanillas, Lasse Suominen, Takahiro Yamazaki, Hui-Hsuan Kuo, Jenna E Moyer, M Laura Martin, Jyothi Manohar, Kihwan Kim, Maria A Sierra, Yusibeska Ramos, Chen Tan, Alexander Emmanuelli, Minkyung Song, Diana K Morales, Dmitriy Zamarin, Melissa K Frey, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Christopher E Mason, Lorenzo Galluzzi, Zhen Ni Zhou, Anna Vähärautio, Suzanne M Cloonan, Juan R Cubillos-Ruiz
{"title":"Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.","authors":"Tito A Sandoval, Camilla Salvagno, Chang-Suk Chae, Deepika Awasthi, Paolo Giovanelli, Matias Marin Falco, Sung-Min Hwang, Eli Teran-Cabanillas, Lasse Suominen, Takahiro Yamazaki, Hui-Hsuan Kuo, Jenna E Moyer, M Laura Martin, Jyothi Manohar, Kihwan Kim, Maria A Sierra, Yusibeska Ramos, Chen Tan, Alexander Emmanuelli, Minkyung Song, Diana K Morales, Dmitriy Zamarin, Melissa K Frey, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Christopher E Mason, Lorenzo Galluzzi, Zhen Ni Zhou, Anna Vähärautio, Suzanne M Cloonan, Juan R Cubillos-Ruiz","doi":"10.1158/2159-8290.CD-23-1451","DOIUrl":null,"url":null,"abstract":"<p><p>Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells toward an immunostimulatory state characterized by the production of type-I IFN and overexpression of molecules that activate NK cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type-I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T-cell-centric modalities. Significance: This study uncovers that targeting dysregulated iron accumulation in ovarian tumors represents a major therapeutic opportunity. Iron chelation therapy using an FDA-approved agent causes immunogenic stress responses in ovarian cancer cells that delay metastatic disease progression and enhance the effects of first-line chemotherapy. See related commentary by Bell and Zou, p. 1771.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"1901-1921"},"PeriodicalIF":29.7000,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11452292/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.CD-23-1451","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Iron accumulation in tumors contributes to disease progression and chemoresistance. Although targeting this process can influence various hallmarks of cancer, the immunomodulatory effects of iron chelation in the tumor microenvironment are unknown. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, unleashes innate immune responses that restrain ovarian cancer. Deferiprone reprogrammed ovarian cancer cells toward an immunostimulatory state characterized by the production of type-I IFN and overexpression of molecules that activate NK cells. Mechanistically, these effects were driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses triggered upon iron chelation. Deferiprone synergized with chemotherapy and prolonged the survival of mice with ovarian cancer by bolstering type-I IFN responses that drove NK cell-dependent control of metastatic disease. Hence, iron chelation may represent an alternative immunotherapeutic strategy for malignancies that are refractory to current T-cell-centric modalities. Significance: This study uncovers that targeting dysregulated iron accumulation in ovarian tumors represents a major therapeutic opportunity. Iron chelation therapy using an FDA-approved agent causes immunogenic stress responses in ovarian cancer cells that delay metastatic disease progression and enhance the effects of first-line chemotherapy. See related commentary by Bell and Zou, p. 1771.
肿瘤中的铁积累会导致疾病进展和化疗耐药性。虽然针对这一过程可以影响癌症的各种特征,但铁螯合在肿瘤微环境中的免疫调节作用尚不清楚。在这里,我们报告了使用美国食品及药物管理局批准的铁螯合剂去铁酮治疗可释放抑制卵巢癌的先天性免疫反应。去铁酮能使卵巢癌细胞重新编程,进入以产生 I 型干扰素(IFN)和过表达激活自然杀伤(NK)细胞的分子为特征的免疫刺激状态。从机理上讲,这些效应是由细胞质中线粒体 DNA 的先天感应和铁螯合引发的核 DNA 损伤反应同时激活所驱动的。去铁酮能与化疗产生协同作用,并通过增强 I 型 IFN 反应延长卵巢癌小鼠的生存期,而 I 型 IFN 反应又能促进 NK 细胞对转移性疾病的依赖性控制。因此,对于目前以 T 细胞为中心的治疗方式难以奏效的恶性肿瘤,螯合铁可能是另一种免疫治疗策略。
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.