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

Background: 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. Methods: Myeloid-specific Egr2 knockout (KO) mice were used to determine roles of macrophage Egr2 signaling in tumor progression and anti-tumor immune responses. RNA-seq analysis and Flow cytometry were used to examine regulation of Egr2 in tumor-associated macrophages (TAMs) and fatty acid-stimulated macrophages. Tumor cell and macrophage admixture study was used to evaluate effects of fatty acid educated macrophages on anti-tumor responses. Results: 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 Conclusions: Our study thus uncovers a novel SA-Egr2 pathway driving macrophage immunosuppression and novel molecular mechanism of OA mediated anti-tumor effect.