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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月9日

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  • Ziling Zhou,
  • Hanyi Zhong,
  • Han Wang,
  • Shoutang Wang,
  • Nan Zhang,
  • Zheng Wang,
  • Renhong Huang,
  • Kunwei Shen

摘要

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.