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

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

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.

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

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Figure 1

Distinct immune microenvironment in human TNBC.

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Distinct immune microenvironment in human TNBC. (A) Schematic of the pat...
(A) Schematic of the patient cohort treated with chemotherapy and immunotherapy, and study design for subsequent analysis. (B) Uniform manifold approximation and projection (UMAP) plot of myeloid cell clusters. (C) UMAP visualization of myeloid cell distribution between responder and nonresponders. (D) Violin plots illustrating AUCell scores for the Hallmark_Inflammatory_Response gene set and the inflammation-resolution gene signature across patient-derived macrophage subclusters. Dashed lines denote the corresponding scores for subcluster hC3_Mac. Pie charts indicate the proportions of responder versus nonresponder cells within each macrophage subcluster. (E) Heatmap depicting average expression levels of neutrophil recruitment genes across patient macrophage populations. Violin plots illustrate the distribution of inflammation resolution gene signature scores (lower left) and neutrophil recruitment signature scores (lower right), with horizontal bars representing the mean values. (F) Composition analysis of macrophage subsets between responders and nonresponders. (G) Pearson correlation analysis of per-patient cell frequencies between human cluster 3 macrophages and cluster 8, 13, 15, and 19 macrophages in responder and nonresponder groups. Shaded areas indicate the 95% confidence interval. Statistical significance was determined using 2-tailed tests. (H) Schematic of the treatment-naive patient cohort and study design. (I) Box plot of macrophage resolution scores in patients with TNBC, stratified into low- and high-inflammation resolution groups. Each point represents the mean resolution score for macrophages from an individual patient. (J) Top Hallmark pathways enriched in epithelial cells of patients with TNBC with low- versus high-inflammation resolution scores. (K) Box plot of epithelial-mesenchymal transition (EMT) scores in patients with TNBC. Each point represents the mean EMT score for epithelial cells from an individual patient. (I and K) A Wilcoxon rank-sum test was used to assess statistical significance between the two groups.