Iron-loaded cancer-associated fibroblasts induce immunosuppression in prostate cancer
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.
Authors
- Kaiyuan Liu (ORCID: https://orcid.org/0000-0002-2396-414X)
- Benxia Hu
- Wei‐Qiang Gao (ORCID: https://orcid.org/0000-0002-0959-2570)
- Luyao Jiang (ORCID: https://orcid.org/0000-0001-7247-9434)
- Helen He Zhu (ORCID: https://orcid.org/0000-0003-0290-5527)
- Guanglei Zhuang (ORCID: https://orcid.org/0000-0001-8141-5096)
- Kai Zhang (ORCID: https://orcid.org/0000-0003-2800-0531)
- Pengcheng Zhang (ORCID: https://orcid.org/0000-0002-4546-0022)
- Wei Xue (ORCID: https://orcid.org/0000-0003-0124-9433)
- Xinyu Chen (ORCID: https://orcid.org/0000-0001-9422-2584)
- Pengfei Ma (ORCID: https://orcid.org/0000-0003-3061-1454)
- Yingchao Zhang (ORCID: https://orcid.org/0000-0002-8078-3142)
- Jinming Wang (ORCID: https://orcid.org/0000-0002-2452-9158)
- Deng Wang (ORCID: https://orcid.org/0000-0003-2062-5828)
- Yujiao Sun
- Penghui Xu (ORCID: https://orcid.org/0009-0006-6462-2193)
- You Wang (ORCID: https://orcid.org/0000-0003-4419-7039)
- Lingling Xiao (ORCID: https://orcid.org/0000-0002-3753-7026)
- Huifang Zhao (ORCID: https://orcid.org/0009-0008-7617-461X)
- Na Jing (ORCID: https://orcid.org/0009-0009-8848-011X)
- Genyu Du
- Chaping Cheng
- Qi Wang (ORCID: https://orcid.org/0009-0004-6707-6613)
Institutions
- Kunming Institute of Zoology (CN)
- Renji Hospital (CN)
- ShanghaiTech University (CN)
- Shanghai University of Traditional Chinese Medicine (CN)
- Shanghai Cancer Institute (CN)
- Seventh People's Hospital of Shanghai (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-20
- DOI
- https://doi.org/10.1038/s41467-024-53233-1
- Citations
- 19
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 7.35
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Shanghai Municipal Education Commission
- Shanghai Jiao Tong University
- Higher Education Discipline Innovation Project
- Renji Hospital
- School of Medicine, Shanghai Jiao Tong University