Perturbing local steroidogenesis to improve breast cancer immunity

Breast cancer, particularly triple-negative breast cancer (TNBC), evades the body's immune defences, in part by fostering an immunosuppressive tumour microenvironment. We present evidence that suppressing local steroidogenesis can enhance anti-tumour immunity against TNBC. Through targeted metabolomics of steroids alongside immunohistochemistry techniques, we initially profiled the presence of various steroids in TNBC patient tumours and identified steroidogenic activity in regions with immune infiltration. In mice, genetic inhibition of immune cell steroidogenesis limited TNBC tumour progression, significantly reducing immunosuppressive components such as tumour-associated macrophages, as revealed by single-cell RNA sequencing. Crucially, inhibiting steroidogenesis seems to strengthen anti-tumour immune responses in dendritic cells and T cells by obstructing glucocorticoid signalling, according to RNA sequencing insights. By undertaking metabolic modelling of the single-cell transcriptomics and targeted tumour steroidomics, we identified mast cells and basophils as the primary steroidogenic agents in TNBC, offering pathways for enhanced therapeutic precision. Overall design: The immunosuppressive tumour microenvironment (TME) of triple-negative breast cancer (TNBC) undermines the efficacy of immunotherapies. The role of steroids in this immunosuppression remains incompletely understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) of CD45+ immune cells from TNBC tumours in Cyp11a1^fl/fl Vav1Cre and control mice, investigating how genetic inhibition of immune cell steroidogenesis impedes tumour progression by notably reducing immunosuppressive elements. Further, RNA sequencing of glucocorticoid-treated and untreated human dendritic cells (DCs) revealed that glucocorticoids inhibit immune-activating factors in DCs, thereby weakening their capacity to stimulate T cells. By undertaking metabolic modelling of the single-cell transcriptomics from CD45+mCherry+/- immune cells in TNBC tumours from Cyp11a1-mCherry reporter mice, we identified mast cells as the primary steroidogenic contributors in TNBC, offering avenues for increased therapeutic precision.