Targeting glucocorticoid receptor to enhance immunotherapy response in triple negative breast cancer

BACKGROUND: Immune checkpoint blockade (ICB) therapies for triple negative breast cancer (TNBC) have yielded limited clinical benefits, which may be attributed to the immunosuppressive tumor immune microenvironment (TIME). Glucocorticoid receptor (GR) has long been thought to suppress immunity by acting on immune cells in the TIME, but no studies have investigated its function in TNBC immunotherapy. METHODS: To investigate the correlation between GR expression and the TIME, we integrated multi-omics data from The Cancer Genome Atlas (TCGA) program, Gene Expression Omnibus (GEO) database, and clinical patient cohorts. Functional validation was performed using an immunocompetent orthotopic murine TNBC model to assess the biological role of GR in tumor progression and immune regulation. Mechanistically, dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) were employed to dissect the transcriptional regulatory mechanisms of GR. RESULTS: Integrated analysis of TCGA and GEO datasets demonstrated a significant inverse association between GR expression and antitumor immunity in TNBC, characterized by diminished CD8 + T cell infiltration, upregulated PD-L1 expression, and reduced MHC-I presentation. In an immunocompetent orthotopic TNBC model, pharmacological GR inhibition enhanced endogenous tumor immune clearance and potentiated ICB therapy responsiveness. Mechanistic studies revealed GR's dual transcriptional regulation: dual-luciferase reporter and ChIP assays confirmed direct GR binding to the PD-L1 promoter to activate its transcription, while concurrently repressing MHC-I expression via promoter occupancy. CONCLUSION: Our study identifies GR signaling as a tumor-intrinsic immunosuppressive axis in TNBC, transcriptionally activating PD-L1 while repressing MHC-I to drive immune escape. These findings propose GR-targeted therapy combined with immunotherapy as a clinically actionable strategy to reverse immune evasion.