Targeting ADGRG1 in cancer-associated adipocytes reprograms the immunosuppressive microenvironment and enhances immunotherapy responsiveness in triple-negative breast cancer models.
BACKGROUND The adipocyte-rich microenvironment of the breast plays a crucial role in tumor progression, yet the functional heterogeneity of cancer-associated adipocytes (CAAs) and their specific mechanisms in driving immunosuppressive microenvironment and therapy resistance remain inadequately characterized. METHODS We performed an integrated analysis of single-nucleus RNA sequencing (snRNA-seq) data from human adipose tissue and bulk transcriptomic data from the TCGA-BRCA and METABRIC cohorts. A prognostic signature was developed based on transcriptional features of CAA subpopulations. Functional roles of the key gene ADGRG1 were investigated through in vitro co-culture systems and in vivo breast cancer models using genetic knockdown/overexpression and pharmacological inhibition. RESULTS snRNA-seq revealed a distinct CAA subpopulation enriched in aggressive contexts, labeled as HAD7. The HAD7-based signature stratified patients into high- and low-score groups, with the high-score group exhibiting poor survival and an immunosuppressive microenvironment. ADGRG1 was identified as a core driver. In vitro, ADGRG1 in CAAs promoted cancer cell migration, invasion, and epithelial mesenchymal transition. In vivo, adipocyte-specific ADGRG1 enhanced tumor growth, metastasis, and impaired anti-tumor immunity. Mechanistically, ADGRG1 activated a CXCL8-AKT/mTOR signaling axis. Crucially, pharmacological inhibition of ADGRG1 synergized with anti-PD-1 therapy, effectively suppressing tumor growth and metastasis by reversing immunosuppressive microenvironment. CONCLUSIONS Our study identifies ADGRG1 as a master regulator of a pro-tumorigenic CAA subpopulation. Targeting the ADGRG1-CXCL8-AKT/mTOR axis represents a promising stromal-targeting strategy to overcome immunotherapy resistance in breast cancer.