铁是人体必需的生物矿物质。在这里，我们描述了一个载铁癌症相关成纤维细胞的子集，称为 FerroCAF，它利用铁诱导前列腺癌的免疫抑制并预测不利的临床结果。 FerroCAF 分泌骨髓细胞相关蛋白，包括 CCL2、CSF1 和 CXCL1，以招募免疫抑制性骨髓细胞。我们报告了小鼠和人类前列腺癌以及人类肺癌和卵巢癌中存在 FerroCAF，并鉴定了一种保守的细胞表面标记物——脊髓灰质炎病毒受体。从机制上讲，FerroCAF 中铁的积累是由血红素降解过程中 Hmox1 介导的铁释放引起的。细胞内铁激活 Kdm6b（一种铁依赖性表观遗传酶），诱导可接近的染色质状态和骨髓细胞相关蛋白基因的转录。通过抑制 Hmox1/铁/Kdm6b 信号轴来靶向 FerroCAF 可产生抗肿瘤免疫和肿瘤抑制。总的来说，我们报告了一个载铁的 FerroCAF 簇，它通过铁依赖性表观遗传重编程机制驱动免疫抑制，并揭示了增强抗肿瘤免疫力的有希望的治疗靶点。© 2024。作者。

Iron is an essential biomineral in the human body. Here, we describe a subset of iron-loaded cancer-associated fibroblasts, termed as FerroCAFs, that utilize iron to induce immunosuppression in prostate cancer and predict an unfavorable clinical outcome. FerroCAFs secrete myeloid cell-associated proteins, including CCL2, CSF1 and CXCL1, to recruit immunosuppressive myeloid cells. We report the presence of FerroCAFs in prostate cancer from both mice and human, as well as in human lung and ovarian cancers, and identify a conserved cell surface marker, the poliovirus receptor. Mechanistically, the accumulated iron in FerroCAFs is caused by Hmox1-mediated iron release from heme degradation. The intracellular iron activates the Kdm6b, an iron-dependent epigenetic enzyme, to induce an accessible chromatin state and transcription of myeloid cell-associated protein genes. Targeting the FerroCAFs by inhibiting the Hmox1/iron/Kdm6b signaling axis incurs anti-tumor immunity and tumor suppression. Collectively, we report an iron-loaded FerroCAF cluster that drives immunosuppression through an iron-dependent epigenetic reprogramming mechanism and reveal promising therapeutic targets to boost anti-tumor immunity.© 2024. The Author(s).