M1 macrophages enhance breast cancer chemoresistance via JAK-STAT3 signaling

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, playing a key role in breast cancer (BrCa) progression and chemotherapy response. While TAMs exhibit diverse phenotypes, the M1/M2 classification remains widely used. M1-like macrophages are known for tumor-killing properties, whereas M2-like macrophages promote tumor growth. However, the impact of TAM subtypes on chemotherapy response remains inconsistent. In this study, we found that M1-like macrophages or their conditioned medium (CM) induced greater BrCa cell death and inhibited proliferation compared to M2-like macrophages. Surprisingly, BrCa cells surviving M1-like macrophage-induced killing displayed increased chemotherapy resistance, independent of proliferation. Transcriptomic profiling indicated upregulation of the JAK–STAT signaling pathway, with elevated STAT3 phosphorylation subsequently confirmed at the protein level. Inhibition of JAKs with Ruxolitinib reduced STAT3 activation and restored chemotherapy sensitivity. Our findings highlight the dual role of M1-like macrophages, demonstrating both tumoricidal activity and the potential to induce chemotherapy resistance in surviving tumor cells, offering insights for macrophage-targeted therapies.