Progesterone reshapes the tumor immune microenvironment towards macrophage-driven immune suppression in hormone receptor-positive breast cancer

Within the immune compartment, progesterone reduced overall T cell infiltration, shifted CD4⁺ T cells toward a regulatory phenotype, and increased macrophages. Notably, lipid-associated macrophages (LAMs) with a high Apoe/Trem2 signature were markedly expanded and engaged in immunosuppressive Spp1–CD44 signaling with immune cells. CellChat analysis of inferred ligand–receptor interactions revealed LAM-driven communication networks that may impair the anti-tumor immune response.

Analysis of human breast cancer scRNA-seq datasets confirmed that PRhi tumors harbored more LAMs than PRlo tumors, supporting the translational relevance of our findings. Collectively, these data establish progesterone signaling as a driver of immune suppression in HR⁺ breast cancer through coordinated effects on tumor cells, T cells, and macrophages. Targeting PR signaling or LAM subsets may represent novel therapeutic strategies to overcome immune evasion and sensitize HR⁺ tumors to immunotherapy.