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Perturbing local steroidogenesis to improve breast cancer immunity

Author

Listed:
  • Qiuchen Zhao

    (University of Cambridge
    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
    University of Cambridge)

  • Bidesh Mahata

    (University of Cambridge)

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.

Suggested Citation

  • 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, 2025. "Perturbing local steroidogenesis to improve breast cancer immunity," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59356-3
    DOI: 10.1038/s41467-025-59356-3
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    References listed on IDEAS

    as
    1. Giovanni Sorrentino & Naomi Ruggeri & Alessandro Zannini & Eleonora Ingallina & Rebecca Bertolio & Carolina Marotta & Carmelo Neri & Elisa Cappuzzello & Mattia Forcato & Antonio Rosato & Miguel Mano &, 2017. "Glucocorticoid receptor signalling activates YAP in breast cancer," Nature Communications, Nature, vol. 8(1), pages 1-14, April.
    2. Bidesh Mahata & Jhuma Pramanik & Louise Weyden & Krzysztof Polanski & Gozde Kar & Angela Riedel & Xi Chen & Nuno A. Fonseca & Kousik Kundu & Lia S. Campos & Edward Ryder & Graham Duddy & Izabela Walcz, 2020. "Tumors induce de novo steroid biosynthesis in T cells to evade immunity," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
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