Immune landscape in invasive ductal and lobular breast cancer reveals a divergent macrophage-driven microenvironment

T cell-centric immunotherapies have shown modest clinical benefit thus far for estrogen receptor-positive (ER⁺) breast cancer. Despite accounting for 70% of all breast cancers, relatively little is known about the immunobiology of ER⁺ breast cancer in women with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC). To investigate this, we performed phenotypic, transcriptional and functional analyses for a cohort of treatment-naive IDC (n = 94) and ILC (n = 87) tumors. We show that macrophages, and not T cells, are the predominant immune cells infiltrating the tumor bed and the most transcriptionally diverse cell subset between IDC and ILC. Analysis of cellular neighborhoods revealed an interplay between macrophages and T cells associated with longer disease-free survival in IDC but not ILC. Our datasets provide a rich resource for further interrogation into immune cell dynamics in ER⁺ IDC and ILC and highlight macrophages as a potential target for ER⁺ breast cancer.