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<p>Chemoresistance remains a critical challenge in breast cancer (BC) treatment. By integrating multi-omics (single-cell, spatial, and bulk transcriptomics) with clinical validation, we identified a specific COL3A<sup>high</sup> CAF subset that drives BC chemoresistance. Mechanistically, these CAFs undergo lipid metabolic reprogramming, secreting excess oleic acid via SCD. This oleic acid binds to ENO1 on tumor cells, activating the PI3K/Akt pathway and inhibiting chemotherapy-induced apoptosis. Simultaneously, COL3A<sup>high</sup> CAFs orchestrate an immunosuppressive niche by recruiting regulatory T cells and impairing cytotoxic CD8<sup>+</sup> T cells. Our findings establish COL3A<sup>high</sup> CAFs as key mediators of resistance through metabolic symbiosis and immune evasion. The strong correlation between COL3A<sup>high</sup> CAF abundance and clinical poor response highlights their potential as both predictive biomarkers and therapeutic targets to overcome chemoresistance in BC patients.</p>

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COL3A1high cancer-associated fibroblasts orchestrate metabolic and immune microenvironments to confer chemoresistance in breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月23日

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  • Peicheng Jiang,
  • Xinyan Li,
  • Ziyi Wang,
  • Su Li,
  • Yonglian Huang,
  • Ye-Xiong Li,
  • Yuqiong Chen,
  • Xiangyu Sun

摘要

Chemoresistance remains a critical challenge in breast cancer (BC) treatment. By integrating multi-omics (single-cell, spatial, and bulk transcriptomics) with clinical validation, we identified a specific COL3Ahigh CAF subset that drives BC chemoresistance. Mechanistically, these CAFs undergo lipid metabolic reprogramming, secreting excess oleic acid via SCD. This oleic acid binds to ENO1 on tumor cells, activating the PI3K/Akt pathway and inhibiting chemotherapy-induced apoptosis. Simultaneously, COL3Ahigh CAFs orchestrate an immunosuppressive niche by recruiting regulatory T cells and impairing cytotoxic CD8+ T cells. Our findings establish COL3Ahigh CAFs as key mediators of resistance through metabolic symbiosis and immune evasion. The strong correlation between COL3Ahigh CAF abundance and clinical poor response highlights their potential as both predictive biomarkers and therapeutic targets to overcome chemoresistance in BC patients.