Perturbing local steroidogenesis to improve breast cancer immunity

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 () and Bidesh Mahata ()
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Qiuchen Zhao: University of Cambridge
Jhuma Pramanik: University of Cambridge
Yongjin Lu: Shandong First Medical University and Shandong Academy of Medical Sciences
Natalie Z. M. Homer: University of Edinburgh
Charlotte J. Imianowski: University of Cambridge
Baojie Zhang: University of Cambridge
Muhammad Iqbal: University of Cambridge
Sanu Korumadathil Shaji: University of Cambridge
Andrew Conway Morris: University of Cambridge
Rahul Roychoudhuri: University of Cambridge
Klaus Okkenhaug: University of Cambridge
Pengfei Qiu: Shandong First Medical University and Shandong Academy of Medical Sciences
Bidesh Mahata: University of Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59356-3

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