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Steroid hormones as modulators of anti-tumoural immunity

Nature Reviews Endocrinology volume 21, pages 331–343 (2025)Cite this article

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Abstract

Immune evasion is a hallmark of cancer progression but the role of steroid hormones in this evasion has long been underrated. This oversight is particularly notable for glucocorticoids given that exogenous glucocorticoids remain a cornerstone therapy in various oncological treatment regimens, supportive care and treatment of immune-related adverse events caused by immune-checkpoint inhibitors. Cortisol, the main endogenous glucocorticoid in humans, is secreted by the adrenal cortex in response to stress. Additionally, cortisol and its inactive metabolite cortisone can be interconverted to further modulate tissue-dependent glucocorticoid action. In the past 5 years, intratumoural production of glucocorticoids, by both immune and tumour cells, has been shown to support tumour immune evasion. Here, we summarize current progress at the crossroads of endocrinology and immuno-oncology. We outline the known effects of steroid hormones on different immune cell types with a focus on glucocorticoids and androgens. We conclude with options for pharmaceutical intervention, including the engineering of cell-based therapies that resist the immunosuppressive action of steroid hormones. Overall, local steroid production and metabolism are emerging elements of tumour immune suppression that are potentially amenable to therapeutic intervention. Targeting steroid hormones to enhance anticancer therapies could increase their efficacy but will require expertise in endocrine care.

Key points

  • High-dose or long-term glucocorticoid use can compromise immunotherapy efficacy.

  • Both immune cells and tumour cells potentially possess the capability to engage in steroid hormone synthesis.

  • Identifying a dependable biomarker could help pinpoint tumours that are likely to respond well to glucocorticoid-modulating therapies.

  • Therapeutic strategies could involve targeting steroid hormone pathways through various approaches, including inhibition of cortisol and androgen synthesis (via CYP11B1 and CYP17A1 inhibitors), blocking cortisol activation (with HSD11B1 inhibitors), or antagonizing glucocorticoid and androgen receptors.

  • When using high-dose systemic inhibitors of steroid hormone synthesis, glucocorticoid replacement is necessary, but this replacement, along with potential reactivation by HSD11B1, might inadvertently lead to unwanted glucocorticoid effects in the tumour microenvironment.

  • Cell-targeted drug delivery and cell-based therapies will enable precise treatment by selectively blocking steroid hormone signalling in effector cells, avoiding the risks of systemic glucocorticoid deficiency.

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Fig. 1: Physiology of glucocorticoid synthesis and interconversion.
Fig. 2: An overview of glucocorticoid and androgen signalling.
Fig. 3: Role of steroid hormones in macrophage polarization and metabolic reprogramming of macrophages.
Fig. 4: Overview of immune cells within the TME.
Fig. 5: Sources of glucocorticoids and their effect on immune cells.

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Acknowledgements

This work resulted, in part, from collaborative work on a grant application on the topic that finally did not receive funding. Work in the authors’ laboratories was supported by the German Research Consortium (Deutsche Forschungsgemeinschaft) within the collaborative research centres SFB Transregio no. TRR205 (project number 314061271) to F.B. and M.K., TRR 388 (project number 452881907) to S.T. and S.K., and an individual grant No. 391587558 (to S.T.). S.K. is funded by the Bavarian Cancer Research Center (TANGO), the Deutsche Forschungsgemeinschaft (grant number: KO5055-2-1 and KO5055/3-1), the international doctoral programme ‘i-Target: immunotargeting of cancer’ (funded by the Elite Network of Bavaria), the Melanoma Research Alliance (grant number 409510), Marie Sklodowska-Curie Training Network for Optimizing Adoptive T Cell Therapy of Cancer (funded by the Horizon 2020 programme of the European Union; grant 955575), Else Kröner-Fresenius-Stiftung (IOLIN), German Cancer Aid (AvantCAR.de), the Wilhelm-Sander-Stiftung, Ernst Jung Stiftung, Institutional Strategy LMUexcellent of LMU Munich (within the framework of the German Excellence Initiative), the Go-Bio-Initiative, the m4-Award of the Bavarian Ministry for Economical Affairs, Bundesministerium für Bildung und Forschung, European Research Council (Starting Grant 756017, CoG 101124203 and PoC Grant 101100460), by the SFB-TRR 338/1 2021–Fritz-Bender Foundation (to S.K.), Deutsche José Carreras Leukämie Stiftung (to S.K.), Hector Foundation, Monika-Kutzner Foundation for Cancer Research (to S.K.), Bavarian Research Foundation (BAYCELLATOR), the Bruno and Helene Jöster Foundation (360° CAR). P.S. received funding from the Else Kröner-Fresenius-Stiftung as part of the clinician-scientist programme “RISE – Rare Important Syndromes in Endocrinology”. S.T. received research grants by the Bruno und Helene Jöster Stiftung, Köln, and the Thomas Kirch Stiftung, München. We further acknowledge structural support from the Bavarian Cancer Research Center and the German Consortium for Translational Cancer Research. G.A. received support from the ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan, the Agence Nationale de la Recherche (18-CE14-0008-01), the French Ministry of Health and the French National Cancer Institute (COMETE-CARE, PRT-K 2020-15367), the SIRIC CARPEM (CAncer Research for PErsonalized Medicine), and COST Action CA20122 Harmonisation.

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Authors and Affiliations

  1. Department of Medicine IV, LMU University Hospital, LMU Munich, Munich, Germany

    Paul Schwarzlmueller, Alexandra Triebig, Tanja Maier, Felix Beuschlein & Matthias Kroiss

  2. Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France

    Guillaume Assié

  3. Department of Endocrinology and National Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Paris, France

    Guillaume Assié & Anne Jouinot

  4. Université Paris Cité, Institut Cochin, Paris, France

    Anne Jouinot

  5. Department of Medicine III and Comprehensive Cancer Center (CCC Munich LMU), LMU University Hospital, Munich, Germany

    Sebastian Theurich

  6. Cancer- and Immunometabolism Research Group, Gene Center, Ludwig Maximilian University (LMU), Munich, Germany

    Sebastian Theurich

  7. Bavarian Cancer Research Center (BZKF), Munich, Germany

    Sebastian Theurich & Matthias Kroiss

  8. German Cancer Consortium (DKTK), Munich Site, Heidelberg, Germany

    Sebastian Theurich & Sebastian Kobold

  9. Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), Zurich, Switzerland

    Felix Beuschlein

  10. The LOOP Zurich - Medical Research Center, Zurich, Switzerland

    Felix Beuschlein

  11. Division of Clinical Pharmacology, LMU University Hospital, LMU Munich, Munich, Germany

    Sebastian Kobold

  12. Kroiss Endokrinologie & Diabetologie, Schweinfurt, Germany

    Matthias Kroiss

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Contributions

All authors researched data for the article. All authors contributed substantially to discussion of the content. M.K., P.S., A.T., G.A., A.J., S.T., F.B. and S.K. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Matthias Kroiss.

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Competing interests

M.K. has received institutional remuneration (to institution) for contract research from Corcept, Inc. S.K. has received honoraria from Cymab, Plectonic, TCR2 Inc., Novartis, BMS, Miltenyi and GSK. S.K. is an inventor of several patents in the field of immuno-oncology. S.K. received license fees from TCR2 Inc. and Carina Biotech. S.K. received research support from Tabby Therapeutics, TCR2 Inc., Plectonic GmBH, Catalym GmBH and Arcus Bioscience for work unrelated to the manuscript.

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Schwarzlmueller, P., Triebig, A., Assié, G. et al. Steroid hormones as modulators of anti-tumoural immunity. Nat Rev Endocrinol 21, 331–343 (2025). https://doi.org/10.1038/s41574-025-01102-2

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