Abstract
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.
Data availability
The sequencing data utilized in this study are publicly available from the databases referenced in the manuscript. Other data supporting the findings are available from the corresponding author upon reasonable request.
Code availability
Relevant code is accessible through the corresponding author(s) upon reasonable request.
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Acknowledgements
We would like to express our gratitude to all the patients who participated in this study. This work was supported by National Natural Science Foundation of China (82403430), the Technology Program Joint Fund of Liaoning Province (2023-BSBA-207), Oncology Project of Liaoning Cancer Hospital (2024-ZLKF-09), Tianjin Key Medical Discipline Construction Project (TJYXZDXK-3-003A) and Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0502200).
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P.J.: Conceptualization, methodology, formal analysis, investigation, data curation, visualization, writing—original draft. X.L.: Investigation, methodology, visualization, writing—original draft, funding acquisition. Z.W.: Investigation, methodology; S.L.: Investigation, writing—editing; Y.H.: Clinical samples collection; Y.L.: Funding acquisition, project administration, resources, supervision; Y.C.: Conceptualization, supervision, validation, writing—review. X.S.: Conceptualization, funding acquisition, project administration, supervision, methodology, investigation, writing—review & editing.
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Jiang, P., Li, X., Wang, Z. et al. COL3A1high cancer-associated fibroblasts orchestrate metabolic and immune microenvironments to confer chemoresistance in breast cancer. npj Precis. Onc. (2026). https://doi.org/10.1038/s41698-026-01338-9
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DOI: https://doi.org/10.1038/s41698-026-01338-9
