Chen Wuzhen, Jiang Mengjie, Zou Xinbo, Chen Zhigang, Shen Lesang, Hu Jianming, Kong Mingxiang, Huang Jian, Ni Chao, Xia Wenjie
Department of Breast Surgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
Oncogene. 2025 Apr 22. doi: 10.1038/s41388-025-03359-3.
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.
表达成纤维细胞活化蛋白的癌症相关成纤维细胞（FAP CAFs）是乳腺癌微环境的关键调节因子，但其免疫调节机制仍知之甚少。通过对单细胞RNA测序数据、临床标本以及体内和体外实验的综合分析，我们确定FAP CAFs是与不良临床结果和免疫抑制特征相关的主要基质细胞群。从机制上讲，FAP CAFs分泌高水平的纤连蛋白1（FN1），其与巨噬细胞上的整合素α5β1结合，触发FAK-AKT-STAT3信号传导，促使巨噬细胞向免疫抑制性M2样表型极化。重要的是，使用西仑吉肽对FN1-整合素α5β1信号进行药理学破坏，有效地重塑了肿瘤免疫格局，并抑制了小鼠模型中的肿瘤生长。这些发现确立了FAP CAF衍生的FN1作为肿瘤免疫抑制的关键协调因子，并确定FN1-整合素α5β1轴是乳腺癌中一个有前景的治疗靶点。
