在所有妇科癌症中，上皮性卵巢癌（OCa）的死亡率最高。尽管付出了一切努力，接受标准手术和细胞毒治疗的个体中 90% 都会出现疾病复发。白血病抑制因子 (LIF) 及其受体 (LIFR) 促进 OCa 进展的确切机制仍不清楚。对癌症数据库的分析表明，LIF 或 LIFR 表达升高与 OCa 患者的无进展生存期较差相关，并且是化疗反应较差的预测因子。使用代表上皮 OCa 的五种亚型的多个原代和已建立的 OCa 细胞系或组织，我们证明了 LIF/LIFR 自分泌信号在 OCa 中活跃。此外，使用 LIFR 抑制剂 EC359 治疗可显着降低 OCa 细胞活力和细胞存活率，IC50 范围为 5-50nM。此外，EC359 降低了 OCa 细胞的干性。使用 RNA-seq 和救援实验的机制研究表明，EC359 主要通过抑制谷胱甘肽抗氧化防御系统来诱导铁死亡。使用多种体外、离体和体内模型，包括基于细胞的异种移植物、患者来源的外植体、类器官和异种移植肿瘤，我们证明 EC359 显着降低了 OCa 的生长和进展。此外，EC359疗法通过强劲的CD45白细胞肿瘤浸润和将肿瘤相关巨噬细胞（TAM）极化为M1表型，显着改善了肿瘤免疫原性，同时对正常T、B和其他免疫细胞没有影响。总的来说，我们的研究结果表明，LIF/LIFR 自分泌环路在 OCa 进展中发挥着重要作用，EC359 可能是一种有前景的 OCa 治疗剂。© 2024。作者。

Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.© 2024. The Author(s).