Iron accumulation in tumors contributes to disease progression and chemoresistance. While 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 towards an immunostimulatory state characterized by production of type I interferon (IFN) and overexpression of molecules that activate natural killer (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.

中文翻译：

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铁螯合疗法引发转移性卵巢癌的先天免疫控制


肿瘤中铁的积累有助于疾病进展和化疗耐药。虽然靶向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。在此，我们报告使用去铁酮（FDA 批准的铁螯合剂）治疗可释放抑制卵巢癌的先天免疫反应。去铁酮将卵巢癌细胞重编程为免疫刺激状态，其特征是产生 I 型干扰素 (IFN) 和激活自然杀伤 (NK) 细胞的分子过度表达。从机制上讲，这些效应是由细胞质中线粒体 DNA 的先天感知以及铁螯合引发的核 DNA 损伤反应的伴随激活驱动的。去铁酮与化疗协同作用，通过增强 I 型 IFN 反应来延长卵巢癌小鼠的生存期，从而驱动 NK 细胞依赖性控制转移性疾病。因此，铁螯合可能代表了一种替代免疫治疗策略，用于治疗目前以 T 细胞为中心的治疗方式难以治疗的恶性肿瘤。