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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—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 chemo-immunotherapy, 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE294252 | GEO | 2026/02/05

REPOSITORIES: GEO

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

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