Iron chelation therapy elicits innate immune control of metastatic ovarian cancer

Iron accumulation in cancer cells contributes to malignant progression and chemoresistance. While disrupting this process can influence various hallmarks of cancer, the immunomodulatory effects of chelating iron in tumors remain undefined. Here, we report that treatment with deferiprone, an FDA-approved iron chelator, elicits innate immune responses that control metastatic ovarian cancer. Deferiprone reprogrammed ovarian cancer cells towards an immunostimulatory state characterized by enhanced production of type I interferon (IFN) and surface overexpression of molecules that activate natural killer (NK) cells. Mechanistically, this reprogramming was driven by innate sensing of mitochondrial DNA in the cytosol and concomitant activation of nuclear DNA damage responses evoked upon iron chelation. Deferiprone administration synergized with chemotherapy and prolonged the survival of mice bearing metastatic ovarian cancer by bolstering intratumoral NK cell infiltration and type I IFN responses. Iron chelation may represent an alternative immunotherapeutic approach for malignancies that are normally refractory to T cell-centric modalities. Overall design: This is a sample of cell infiltrate from ovarian cancer ascites

癌细胞内铁蓄积可促进恶性进展与化疗耐药。尽管靶向干预这一过程可影响癌症的多种标志性特征，但肿瘤内铁螯合的免疫调节效应仍未明确。本研究发现，经美国食品药品监督管理局（FDA）批准的铁螯合剂去铁酮（deferiprone）可诱导天然免疫应答，从而抑制转移性卵巢癌。去铁酮可将卵巢癌细胞重编程为免疫激活状态，其特征为I型干扰素（type I interferon）生成增加，以及表面高表达可激活自然杀伤（NK）细胞的分子。机制层面，该重编程过程由胞质线粒体DNA的天然感知，以及铁螯合引发的核DNA损伤应答的协同激活所驱动。去铁酮给药可与化疗产生协同效应，通过增强肿瘤内NK细胞浸润与I型干扰素应答，延长转移性卵巢癌荷瘤小鼠的生存期。对于原本对以T细胞为中心的治疗方案耐药的恶性肿瘤，铁螯合或可成为一种替代免疫治疗策略。实验整体设计：本研究样本取自卵巢癌腹水中的浸润细胞。