Tumor-educated macrophages promote cytokine-driven lung colonization in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) remains one of the most lethal breast cancer subtypes, driven by early dissemination and resistance to therapy. Here, we reveal a macrophage-centered cytokine circuit that fuels TNBC metastasis and immune evasion. Tumor cells reprogram naïve macrophages into tumor-associated macrophages (TAMs) that secrete CCL3, CCL4, CXCL2, and IL-1β, collectively promoting epithelial-to-mesenchymal transition, migration, transendothelial invasion, and lung colonization. These TAMs, in turn, convert naïve CD4⁺ T cells into FOXP3⁺ Tregs, establishing a self-reinforcing immunosuppressive niche. Pharmacological inhibition of CCR5, CXCR2, and IL1R1 with maraviroc, navarixin, and anakinra, respectively, disrupted this cytokine axis, suppressing metastatic colonization in vivo. Our findings reveal that blocking cytokine receptor signaling disrupts the pro-metastatic crosstalk between macrophages and TNBC cells, offering a clinically actionable strategy to restrain metastasis and overcome therapy resistance in TNBC.