Fibroblast Activation Protein (FAP)+ cancer-associated fibroblasts induce macrophage M2-like polarization via the Fibronectin 1-Integrin α5β1 axis in breast cancer PMID: 40263422

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
8. Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
9. Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
10. Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
11. Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. [email protected].
12. Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
13. General Surgery, Cancer Center, Department of Breast Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang, China. [email protected].
# 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.