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.
Nature communications. 2024 Oct 20*** epublish ***
Kai Zhang, Kaiyuan Liu, Benxia Hu, Genyu Du, Xinyu Chen, Lingling Xiao, Yingchao Zhang, Luyao Jiang, Na Jing, Chaping Cheng, Jinming Wang, Penghui Xu, You Wang, Pengfei Ma, Guanglei Zhuang, Huifang Zhao, Yujiao Sun, Deng Wang, Qi Wang, Wei Xue, Wei-Qiang Gao, Pengcheng Zhang, Helen He Zhu
State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, and Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Key Laboratory of Genetic Evolution & Animal Models, Kunming Natural History Museum of Zoology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China., Department of Emergency Medicine, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China., Department of Obstetrics and Gynaecology, Shanghai Key Laboratory of Gynaecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., School of Biomedical Engineering, Shanghai Tech University, Shanghai, China., State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center, and Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China. .