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  2. Fibroblast Activation Protein (FAP)+ cancer-associated fibroblasts induce macrophage M2-like polarization via the Fibronectin 1-Integrin α5β1 axis in breast cancer

Fibroblast Activation Protein (FAP)+ cancer-associated fibroblasts induce macrophage M2-like polarization via the Fibronectin 1-Integrin α5β1 axis in breast cancer

  • Oncogene. 2025 Jul;44(28):2396-2412. doi: 10.1038/s41388-025-03359-3.
Wuzhen Chen # 1 2 3 Mengjie Jiang # 4 Xinbo Zou # 5 Zhigang Chen 1 2 Lesang Shen 1 2 Jianming Hu 1 2 Mingxiang Kong 6 Jian Huang 7 8 9 Chao Ni 10 11 12 Wenjie Xia 13
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 2 Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 3 Department of Oncology, Lanxi People's Hospital, Jinhua, Zhejiang, China.
  • 4 Department of Radiotherapy, First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, China.
  • 5 Department of Otolaryngology, First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, China.
  • 6 Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
  • 7 Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. drhuangjian@zju.edu.cn.
  • 8 Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. drhuangjian@zju.edu.cn.
  • 9 Cancer Center, Zhejiang University, Hangzhou, China. drhuangjian@zju.edu.cn.
  • 10 Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. drnichao@zju.edu.cn.
  • 11 Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. drnichao@zju.edu.cn.
  • 12 Cancer Center, Zhejiang University, Hangzhou, China. drnichao@zju.edu.cn.
  • 13 General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China. xiawenjie1031@zju.edu.cn.
  • # Contributed equally.
Abstract

Cancer-associated fibroblasts expressing fibroblast activation protein (FAP+ CAFs) are critical modulators of the breast Cancer microenvironment, yet their immunoregulatory mechanisms remain poorly understood. Through integrated analysis of single-cell RNA Sequencing data, clinical specimens, and in vivo and in vitro experiments, we identified FAP+ CAFs as the predominant stromal population associated with poor clinical outcomes and immunosuppressive features. Mechanistically, FAP+ CAFs secrete high levels of fibronectin 1 (FN1), which engages Integrin α5β1 on macrophages to trigger FAK-AKT-STAT3 signaling, driving their polarization toward an immunosuppressive M2-like phenotype. Importantly, pharmacological disruption of FN1-integrin α5β1 signaling using Cilengitide effectively reprogrammed the tumor immune landscape and suppressed tumor growth in mice models. These findings establish FAP+ CAF-derived FN1 as a critical orchestrator of tumor immunosuppression and identify the FN1-integrin α5β1 axis as a promising therapeutic target in breast Cancer.

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