Iron Chelation Therapy Elicits Innate Immune Control of Metastatic Ovarian Cancer
Tito A. Sandoval, Camilla Salvagno, Chang-Suk Chae, Deepika Awasthi, Paolo Giovanelli, Matías Marín Falco, Sung‐Min Hwang, Elí Terán-Cabanillas, Lasse Suominen, Takahiro Yamazaki, Hui–Hsuan Kuo, Jenna E. Moyer, M. Laura Martín, 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
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.