Single-cell multi-omics deciphers the myofibro-inflammatory program of cancer-associated fibroblasts in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype associated with poor prognosis and limited therapeutic options, largely due to its unique tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) critically influence tumor progression and metastasis, yet their functional heterogeneity in TNBC remain poorly understood. An integrated multi-omic analysis was conducted using single-cell RNA sequencing and single-cell ATAC sequencing from TNBC and hormone receptor-positive/HER2-negative (HR + HER2-) breast cancers. The signaling axis was validated critically regulates both TNBC progression and CAF subtype switching. We identified a distinct CAF subpopulation, termed my_iCAFs, characterized by co-expression of myofibroblastic (FAP, ACTA2) and inflammatory markers (CXCL12), significantly enriched within the TNBC TME. My_iCAFs possess elevated activity of pathways involved in epithelial-mesenchymal transition, PI3K/AKT signaling, and pro-inflammatory TNF/NF-κB signaling. Multi-omic integration pinpointed FOSB as a central transcription factor whose expression and chromatin accessibility were selectively enhanced in my_iCAFs, potentially regulated by tumor-derived CXCL8 signaling via syndecan receptors. Also, we found that the FOSB-HES1 axis can effectively activate the transition of CAFs into my_iCAFs. This study reveals a novel FOSB-driven myofibroinflammatory CAF subtype prominently enriched in TNBC, suggesting crucial roles in tumor aggressiveness and highlighting potential therapeutic targets within the stromal compartment of this challenging breast cancer subtype.