<p>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.</p><p></p>