Multiplatform single-cell and spatial transcriptomics reveal sex-specific malignant states and architecture in male breast cancer

Abstract

Male breast cancer (MBC) is rare and remains largely managed using knowledge derived from female breast cancer. Here, we generated a multiplatform single-cell and spatial transcriptomic atlas integrating scRNA-seq, SeekSpace, Visium HD, Xenium In Situ, and multiplex immunohistochemistry data from male and female breast cancer cohorts, covering more than 660,000 cells. We identified male-specific tumor cells (MSTCs) that were enriched in MBC, rare in female breast cancer, and associated with poorer disease-free survival. MSTCs exhibited neural transcriptional programs, increased transcriptome-inferred copy number variation burden, and spatial coupling with fatty acid metabolism signals. MSTC-enriched regions showed reduced antigen-presentation signatures and spatial association with APOE+/CD163+ macrophages, with GRN-SORT1 emerging as a candidate macrophage-tumor interaction axis. These findings define an MBC-associated malignant state and its immune-metabolic spatial context.