Inflammation- and Resolution-Programmed Myeloid Circuits Govern Therapeutic Resistance in Epithelial and Mesenchymal Triple-Negative Breast Cancer

Authors

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

Language

English

Publication Date

4-15-2026

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI198815

PMID

41701526

PMCID

PMC13078875

PubMedCentral® Posted Date

2-17-2026

PubMedCentral® Full Text Version

Post-print

Abstract

Single-cell analysis of human triple-negative breast cancer revealed heterogeneous macrophage populations with opposing phenotypes - proinflammatory and proresolution 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 proresolution macrophages were enriched in mesenchymal-like tumors. Mouse models faithfully recapitulated these patterns. After chemoimmunotherapy, mesenchymal-like tumors expanded proresolution 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.

Keywords

Humans, Animals, Female, Triple Negative Breast Neoplasms, Mice, Inflammation, Macrophages, Drug Resistance, Neoplasm, Neutrophils, Specialized Pro-Resolving Mediators, Immunology, Oncology, Breast cancer, Cancer immunotherapy, Macrophages

Published Open-Access

yes

Recommended Citation

Yu, Liqun; Rivas, Charlotte; Liu, Fengshuo; et al., "Inflammation- and Resolution-Programmed Myeloid Circuits Govern Therapeutic Resistance in Epithelial and Mesenchymal Triple-Negative Breast Cancer" (2026). Faculty, Staff and Students Publications. 7076.
https://digitalcommons.library.tmc.edu/baylor_docs/7076