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 m
APA
Yang L, Chen Z, et al. (2026). Targeting glucocorticoid receptor to enhance immunotherapy response in triple negative breast cancer.. Breast cancer research : BCR, 28(1). https://doi.org/10.1186/s13058-026-02230-x
MLA
Yang L, et al.. "Targeting glucocorticoid receptor to enhance immunotherapy response in triple negative breast cancer.." Breast cancer research : BCR, vol. 28, no. 1, 2026.
PMID
41612481
Abstract
[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.
[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.
MeSH Terms
Receptors, Glucocorticoid; Triple Negative Breast Neoplasms; Humans; Female; Animals; Mice; Tumor Microenvironment; Immunotherapy; Gene Expression Regulation, Neoplastic; Cell Line, Tumor; B7-H1 Antigen; Xenograft Model Antitumor Assays; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes
같은 제1저자의 인용 많은 논문 (5)
- Generational trends in reproductive factors among women in the US: implications for breast cancer incidence.
- Prediction of high-risk factor in early-stage lung cancer: micropapillary adenocarcinoma.
- Comprehensive treatment for intracranial invasive sinonasal intestinal-type adenocarcinoma with a focus on radiotherapy dosage and immunological combination therapy: A case report.
- Cancer-associated fibroblasts-derived exosomes in colorectal cancer progression: Mechanism and therapeutic opportunities.
- Effects of Preoperative Mindfulness Training Combined With Active Breathing and Circulation Exercises on Pulmonary Function Recovery in Lung Cancer Patients After Lobectomy.