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<p>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 (<i>FAP</i>, <i>ACTA2</i>) and inflammatory markers (<i>CXCL12</i>), 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 <i>CXCL8</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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

摘要

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.