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

Rongzhi Huang,1,* Zexu Zhan,1,* Shulin Huang,1 Wenlong Cao,1 Jiehua Li,1 Min Mao2 1Department of Gastrointestinal and Gland Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, The Guangxi Zhuang Autonomous Region, 530021, People’s Republic of China; 2Department of Thyroid and Breast Surgery, The First People’s Hospital of Qinzhou, Qinzhou, Guangxi, 535000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jiehua Li, Email lijiehua0109@163.cm Min Mao, Email min15289679719@163.comIntroduction: 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.Methods: 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.Results: 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.Conclusion: 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.Keywords: MMP11, cancer-associated fibroblasts, SPP1, tumor-associated macrophage, crosstalk, breast cancer