Tumor-Promoting Crosstalk of MMP11⁺ Fibroblasts and SPP1⁺ Macrophages Drive Poor Prognosis in Breast Cancer: Integrated Multi-Omics Analysis

<h4>Introduction</h4>Breast cancer (BRCA) remains the leading cause of cancer-related mortality among women and poses significant therapeutic challenges. While the heterogeneity of the tumor microenvironment (TME) is well established as a key contributor to tumor progression and treatment failure, yet the specific stromal-immune interactions driving these processes remain poorly understood.<h4>Methods</h4>We employed an integrated multi-omics approach, combining bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics, to systematically characterize the cellular landscape of the BRCA TME.<h4>Results</h4>Our analysis revealed a distinct population of MMP11⁺ cancer-associated fibroblasts (CAFs). MMP11⁺ CAFs were significantly enriched in BRCA tissues and were associated with unfavorable prognosis. Functional analysis revealed that MMP11⁺ CAFs were associated with tumor progression by enhancing angiogenesis and epithelial-mesenchymal transition (EMT). Moreover, our study uncovered that a significant interaction between MMP11⁺ CAFs and SPP1⁺ macrophages that was strongly associated with poor outcomes. Patients with high MMP11⁺ CAFs and SPP1⁺ macrophages were associated with adverse overall survival and might impaired immunotherapy response.<h4>Conclusion</h4>Our study identifies a distinct population of MMP11⁺ CAFs that is highly enriched in BRCA. We further elucidated a close interaction between MMP11⁺ CAFs and SPP1⁺ macrophages within the BRCA tumor microenvironment. Targeting this stromal-immune interaction represents a promising therapeutic target for future BRCA treatment strategies.