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.