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

Abstract Hormone receptor–positive (HR⁺) breast cancers comprise ~80% of breast cancer cases, yet endocrine resistance remains a clinical barrier. While estrogen receptor alpha (ER) biology is well characterized, the role of progesterone receptor (PR) signaling in tumor progression and immune evasion is less defined. Using the ER⁺/PR⁺ SSM2 murine mammary tumor model, we investigated progesterone’s influence on tumor growth and the immune microenvironment. Progesterone significantly accelerated tumor growth in vivo and enhanced proliferation in vitro. Single-cell RNA sequencing (scRNA-seq) revealed that progesterone treatment reshaped the tumor microenvironment, expanding the tumor cell compartment while markedly reducing immune populations. Tumor-intrinsic analyses showed downregulation of interferon and antigen presentation pathways, alongside upregulation of cell cycle and proliferation signaling. 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 PR hi tumors harbored more LAMs than PR lo 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.