Macrophage polarisation and metabolic reprogramming in cortisol-producing adenomas

Ana Crastin; David Onesimu Ezra Leander; Lorenzo Tucci; Alessandra Mangone; Vittoria Favero; Chiara Parazzoli; Oskar Podstawka; Xu Mengjie; Alessandro Prete; Hardy Rowan S.; Cristina L. Ronchi

doi:10.1530/endoabs.117.CC1

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Endocrine Abstracts (2026) 117 CC1 | DOI: 10.1530/endoabs.117.CC1

SFEBES2026 Featured Clinical Case Posters Section (10 abstracts)

Macrophage polarisation and metabolic reprogramming in cortisol-producing adenomas

Ana Crastin ^1,2,3 , Ezra Leander David Onesimu ¹ , Lorenzo Tucci ^1,4 , Alessandra Mangone ^1,5 , Vittoria Favero ^1,6 , Chiara Parazzoli ⁵ , Oskar Podstawka ⁷ , Xu Mengjie ^1,8 , Alessandro Prete ^1,9 , Rowan S. Hardy ^1,2,3 & Cristina L. Ronchi ^1,9

Author affiliations

¹Department of Metabolism and Systems Science, Birmingham, United Kingdom; ²Department of Biomedical Sciences, University of Birmingham, Birmingham, United Kingdom; ³National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, United Kingdom; ⁴Medical and Surgical Sciences Department, Alma Mater Studiorum University of Bologna, Bologna, Italy; ⁵Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; ⁶Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy; ⁷Cancer Research UK Clinical Trials Unit (CRCTU), Birmingham, United Kingdom; ⁸Taihe Hospital, Hubei University of Medicine, Shiyan, China; ⁹Department of Endocrinology, Queen Elizabeth Hospital Birmingham NHS Trust, Birmingham, United Kingdom

Background: Endogenous Cushing’s syndrome (CS) is characterised by chronic cortisol excess, profoundly altering immune responses and host defence mechanisms. However, its direct effects on tissue macrophage phenotype and metabolism remain undefined. The impact of mild autonomous cortisol secretion (MACS) in cortisol-producing adrenocortical adenomas (CPA) without clinical CS features is unclear. We hypothesised that macrophage polarisation, activation, and bioenergetic function are altered in both CPA-CS and CPA-MACS.

Methods: Human macrophages were polarised into M1-like inflammatory state using TNFα (10 ng/ml) and IFNγ (20 ng/ml) and co-treated with 10% patient serum. Samples were obtained from 18 patients (12CPA-MACS [8 women], 6CPA-CS [4 women]) and 10 age- and sex-matched controls with endocrine-inactive adenomas (EIA). Cytokine levels and gene expression were analysed by ELISA and RT-qPCR. Mitochondrial viability (MTT assay) and phagocytosis were assessed after 48 hours. Data were correlated with cortisol secretion and tumour characteristics.

Results: Pro-inflammatory IL6 secretion was reduced in macrophages treated with CPA-MACS (0.72-fold,P = 0.071) and CPA-CS serum (0.50-fold, P = 0.004) compared with EIA, while IL6 mRNA showed a similar trend. The M2 marker CD163 modestly increased in CPA-CS (1.32-fold,P = 0.258) but not in CPA-MACS, correlating with post-dexamethasone cortisol levels and tumour size. TGFβ concentrations were significantly elevated in CPA-CS (P = 0.012), and IL6/CD163 ratio increased (2.41-fold,P = 0.003), indicating a cortisol-dependent shift toward an anti-inflammatory phenotype. Mitochondrial viability increased in CPA-MACS (P = 0.059) and CPA-CS (P = 0.005), accompanied by reduced ATP production and maximal respiration (P < 0.05) and enhanced glycolytic activity (P < 0.01) in CPA-CS. Phagocytosis was impaired in both CPA-MACS (P = 0.014) and CPA-CS (P = 0.076). Glucocorticoid receptor blockade partially restored mitochondrial respiration, spare capacity, and bioenergetic balance.

Conclusions: Both CPA-MACS and CPA-CS sera suppress M1-like macrophage activation and promote M2-like polarisation, impairing phagocytosis and altering mitochondrial metabolism. Even mild cortisol excess in MACS significantly modulates macrophage function, potentially contributing to systemic immune dysregulation and altered tissue homeostasis.