Tumor-derived stearic acid induces macrophage Egr2 signaling to suppress anti-tumor immunity in breast cancer

Authors

Ning, Y., Wu, C., Phuyal, S., Hu, X., Li, H., Mitchell, R., Yan, J., Ding, C.

Abstract

Macrophages in breast cancer are highly heterogeneous and targeting both tissue-resident and bone marrow-derived macrophages represents a high-potential strategy in breast cancer immunotherapy. Here we showed that early growth response 2 (Egr2) was highly expressed in mammary tissue macrophages and recruited macrophages upon tumor progression. Depletion of Egr2 in myeloid cells significantly decreased the immunosuppressive function of polarized M2-like macrophages and TAMs. Tumor progression was delayed in myeloid cell Egr2 knockout mice, which was associated with enhanced function of effector CD8+ T cells and NK cells. Mechanistically, we showed that retinol and nicotinamide metabolism in TAMs were impaired after Egr2 depletion. Further, tumor cell-derived stearic acid (SA) was identified as an important fatty acid inducing Egr2 expression. SA stimulation induced macrophage-mediated immunosuppression in an Egr2 dependent manner. Addition of oleic acid (OA) uniquely repressed SA-induced Egr2 expression and immunosuppressive activity in macrophages. Our study thus uncovers a novel SA-Egr2 pathway driving macrophage immunosuppression and novel molecular mechanism of OA mediated anti-tumor effect.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 22 Jul 2026.

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