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ResearchIn-Press PreviewImmunologyOncology Open Access | 10.1172/JCI198815

Inflammation- and resolution-programmed myeloid circuits govern therapeutic resistance in epithelial and mesenchymal triple-negative breast cancer

Liqun Yu,1 Charlotte Rivas,1 Fengshuo Liu,1 Yichao Shen,1 Ling Wu,1 Zhan Xu,1 Yunfeng Ding,1 Xiaoxin Hao,1 Weijie Zhang,1 Hilda L. Chan,1 Jun Liu,1 Bo Wei,2 Yang Gao,1 Luis Becerra-Dominguez,1 Yi-Hsuan Wu,1 Siyue Wang,1 Tobie D. Lee,1 Xuan Li,1 Xiang Chen,1 David G. Edwards,1 and Xiang H.-F. Zhang1

1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

Find articles by Li, X. in: PubMed | Google Scholar

1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, United States of America

2Metabolomics Core Facility, Department of Bioinformatics and Computational , The University of Texas MD Anderson Cancer Center, Houston, United States of America

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Published February 17, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI198815.
Copyright © 2026, Yu et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 17, 2026 - Version history
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Abstract

Single-cell analysis of human triple-negative breast cancer revealed heterogeneous macrophage populations with opposing phenotypes—pro-inflammatory and pro-resolution of inflammation. Paradoxically, both subsets accumulated in therapy-refractory residual tumors but showed inverse correlations across patients, suggesting mutually exclusive resistance mechanisms. Inflammatory macrophages localized preferentially to epithelial-like tumors, whereas pro-resolution macrophages were enriched in mesenchymal-like tumors. Mouse models faithfully recapitulated these patterns. After immuno-chemotherapy, mesenchymal-like tumors expanded pro-resolution macrophages through phagocytosis/efferocytosis, ω-3 fatty-acid uptake, and resolvin production. Macrophage-secreted C1q emerged as a principal antagonist of T-cell function by targeting mitochondria and inducing metabolic dysfunction. By contrast, epithelial-like tumors accumulated inflammatory macrophages and neutrophils that produced prostaglandins via ω-6 fatty-acid pathways. Knocking down ELOVL5—an elongase involved in ω-3 and ω-6 metabolism—mitigated both neutrophil- and macrophage-mediated immunosuppression. These distinct axes, driven by dysregulated inflammation and resolution programs, converged to undermine therapy-induced immunosurveillance; however, targeting their shared upstream regulators may overcome these resistance mechanisms.

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  • Version 1 (February 17, 2026): In-Press Preview
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