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

Authors

Min Li, Jun Lin, Changwei Yang, Jiaqi Yang, Caiqin Mo, Zhishuo Zhang, Anping Liu, Wei Lin, Lin Lin, Wanglong Li, Yiqiu Wang, Xinhuang Hou

Published in

Cell death discovery. Jul 11, 2026. Epub Jul 11, 2026.

Abstract

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.

PMID:
42436124
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.

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