biostudies-literatureSandoval TAStand Up To CancerCancer Research Institute (CRI)The Ovarian Cancer Research AllianceThe Cancer Foundation FinlandStand Up To Cancer (SU2C)National Institutes of Health (NIH)NIAID NIH HHSU.S. Department of Defense (DOD)National Research Foundation of KoreaNational Institutes of HealthMarie Skłodowska-Curie grantCancer Research InstituteNational Research Foundation of Korea (NRF)PerMed JTC2020 PARIS/Academy of FinlandAmerican Association for Cancer Research (AACR)U.S. Department of DefenseFoundation for the Finnish Cancer InstituteNCI NIH HHSNational Cancer Center, KoreaNINDS NIH HHSAmerican Association for Cancer ResearchThe Sigrid Jusélius Foundation1901-1921https://www.ebi.ac.uk/biostudies/studies/S-EPMC11452292biostudies-literatureUnknown14(10)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.Cancer discoveryIron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.PMC11452292BC180476P1N/A344697lPostdoctoral Fellowship AwardW81XWH-16-1-043822-40-15-HWANR01 CA249054F31 CA257631BC210945W81XWH2110478W81XWH2110357R01 CA271619101067835R01 CA271915SU2C-AACR-IRG-03-16RS-2023-00213292R01 CA282072NCC-19112605T32 AI134632T32 5T32AI134632-02SU2C-AACR-PS-24MSIT 2020R1C1C1010303W81XWH-22-OCRP-IIRAK. Albin Johansson Cancer Research FellowshipW81XWH2010191R01 NS114653F31CA257631Salvagno CCantillo EKuo HHEmmanuelli AAwasthi DManohar JKim KVaharautio AHolcomb KHwang SMChapman-Davis ESong MCubillos-Ruiz JRTeran-Cabanillas ESandoval TAGiovanelli PMarin Falco MFrey MKMartin MLRamos YCloonan SMZamarin DMason CETan CMorales DKNi Zhou ZSuominen LChae CSGalluzzi LMoyer JEYamazaki TSierra MAfalseIron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer.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. 1771.2024-01-01T00:00:00Z2024 Oct2026-06-02T11:54:01.437Z2025-07-01T03:05:38.899ZS-EPMC114522923907308510.1158/2159-8290.CD-23-145110.1158/2159-8290.cd-23-1451