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
Figure 3
Resistant mesenchymal-like tumors promote tumor-associated macrophage differentiation.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)