2026/02/17 by Liqun Yu, Charlotte Rivas, Fengshuo Liu +18 · 1 voice
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · #Immune cells in cancer #Phagocytosis and Immune Regulation #Single-cell and spatial transcriptomics
paper · pdf · doi:10.1172/jci198815
openalex publication_date 2026/02/17 · openalex created_date 2026/02/18 · openalex updated_date 2026/08/03
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.