Perturbing local steroidogenesis to improve breast cancer immunity
Abstract Breast cancer, particularly triple-negative breast cancer (TNBC), evades the body’s immune defences, in part by cultivating an immunosuppressive tumour microenvironment. Here, we show that suppressing local steroidogenesis can augment anti-tumour immunity against TNBC. Through targeted meta...
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| Format: | Article |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59356-3 |
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| author | Qiuchen Zhao Jhuma Pramanik Yongjin Lu Natalie Z. M. Homer Charlotte J. Imianowski Baojie Zhang Muhammad Iqbal Sanu Korumadathil Shaji Andrew Conway Morris Rahul Roychoudhuri Klaus Okkenhaug Pengfei Qiu Bidesh Mahata |
| author_facet | Qiuchen Zhao Jhuma Pramanik Yongjin Lu Natalie Z. M. Homer Charlotte J. Imianowski Baojie Zhang Muhammad Iqbal Sanu Korumadathil Shaji Andrew Conway Morris Rahul Roychoudhuri Klaus Okkenhaug Pengfei Qiu Bidesh Mahata |
| author_sort | Qiuchen Zhao |
| collection | DOAJ |
| description | Abstract Breast cancer, particularly triple-negative breast cancer (TNBC), evades the body’s immune defences, in part by cultivating an immunosuppressive tumour microenvironment. Here, we show that suppressing local steroidogenesis can augment anti-tumour immunity against TNBC. Through targeted metabolomics of steroids coupled with immunohistochemistry, we profiled the existence of immunosuppressive steroids in TNBC patient tumours and discerned the steroidogenic activity in immune-infiltrating regions. In mouse, genetic inhibition of immune cell steroidogenesis restricted TNBC tumour progression with a significant reduction in immunosuppressive components such as tumour associated macrophages. Steroidogenesis inhibition appears to bolster anti-tumour immune responses in dendritic and T cells by impeding glucocorticoid signalling. Undertaking metabolic modelling of the single-cell transcriptomics and targeted tumour-steroidomics, we pinpointed the predominant steroidogenic cells. Inhibiting steroidogenesis pharmacologically using a identified drug, posaconazole, curtailed tumour expansion in a humanised TNBC mouse model. This investigation paves the way for targeting steroidogenesis and its signalling pathways in breast cancer affected by immune-steroid maladaptation. |
| format | Article |
| id | doaj-art-e12e34e917b1478b900f0085a52eaff1 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e12e34e917b1478b900f0085a52eaff12025-08-20T02:19:57ZengNature PortfolioNature Communications2041-17232025-04-0116111810.1038/s41467-025-59356-3Perturbing local steroidogenesis to improve breast cancer immunityQiuchen Zhao0Jhuma Pramanik1Yongjin Lu2Natalie Z. M. Homer3Charlotte J. Imianowski4Baojie Zhang5Muhammad Iqbal6Sanu Korumadathil Shaji7Andrew Conway Morris8Rahul Roychoudhuri9Klaus Okkenhaug10Pengfei Qiu11Bidesh Mahata12Department of Pathology, University of CambridgeDepartment of Pathology, University of CambridgeBreast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical SciencesMass Spectrometry Core, Edinburgh Clinical Research Facility, Queens Medical Research Institute, University of EdinburghDepartment of Pathology, University of CambridgeDepartment of Pathology, University of CambridgeDepartment of Pathology, University of CambridgeDepartment of Pathology, University of CambridgeDepartment of Pathology, University of CambridgeDepartment of Pathology, University of CambridgeDepartment of Pathology, University of CambridgeBreast Cancer Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical SciencesDepartment of Pathology, University of CambridgeAbstract Breast cancer, particularly triple-negative breast cancer (TNBC), evades the body’s immune defences, in part by cultivating an immunosuppressive tumour microenvironment. Here, we show that suppressing local steroidogenesis can augment anti-tumour immunity against TNBC. Through targeted metabolomics of steroids coupled with immunohistochemistry, we profiled the existence of immunosuppressive steroids in TNBC patient tumours and discerned the steroidogenic activity in immune-infiltrating regions. In mouse, genetic inhibition of immune cell steroidogenesis restricted TNBC tumour progression with a significant reduction in immunosuppressive components such as tumour associated macrophages. Steroidogenesis inhibition appears to bolster anti-tumour immune responses in dendritic and T cells by impeding glucocorticoid signalling. Undertaking metabolic modelling of the single-cell transcriptomics and targeted tumour-steroidomics, we pinpointed the predominant steroidogenic cells. Inhibiting steroidogenesis pharmacologically using a identified drug, posaconazole, curtailed tumour expansion in a humanised TNBC mouse model. This investigation paves the way for targeting steroidogenesis and its signalling pathways in breast cancer affected by immune-steroid maladaptation.https://doi.org/10.1038/s41467-025-59356-3 |
| spellingShingle | Qiuchen Zhao Jhuma Pramanik Yongjin Lu Natalie Z. M. Homer Charlotte J. Imianowski Baojie Zhang Muhammad Iqbal Sanu Korumadathil Shaji Andrew Conway Morris Rahul Roychoudhuri Klaus Okkenhaug Pengfei Qiu Bidesh Mahata Perturbing local steroidogenesis to improve breast cancer immunity Nature Communications |
| title | Perturbing local steroidogenesis to improve breast cancer immunity |
| title_full | Perturbing local steroidogenesis to improve breast cancer immunity |
| title_fullStr | Perturbing local steroidogenesis to improve breast cancer immunity |
| title_full_unstemmed | Perturbing local steroidogenesis to improve breast cancer immunity |
| title_short | Perturbing local steroidogenesis to improve breast cancer immunity |
| title_sort | perturbing local steroidogenesis to improve breast cancer immunity |
| url | https://doi.org/10.1038/s41467-025-59356-3 |
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