Targeting ADGRG1 in cancer-associated adipocytes reprograms the immunosuppressive microenvironment and enhances immunotherapy responsiveness in triple-negative breast cancer models

作者：Ziling Zhou, Hanyi Zhong, Han Wang, Shoutang Wang, Nan Zhang, Zheng Wang, Renhong Huang, Kunwei Shen · 发表于：BMC Medicine · 年份：2026 · DOI：10.1186/s12916-026-05049-7 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Immune cells in cancer、Ferroptosis and cancer prognosis

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 tum...