Multiplatform single-cell and spatial transcriptomics reveal sex-specific malignant states and architecture in male breast cancer
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.
Authors
- Shuqun Zhang (ORCID: https://orcid.org/0000-0002-6998-7849)
- Haibo Wang (ORCID: https://orcid.org/0000-0002-5585-704X)
- Nianzeng Xing (ORCID: https://orcid.org/0000-0002-2696-5279)
- Siyi Chen (ORCID: https://orcid.org/0000-0002-4638-2804)
- Haoyuan Shi (ORCID: https://orcid.org/0000-0002-6028-0185)
- Xiuli Zhang (ORCID: https://orcid.org/0000-0002-5694-0101)
- Zhangjian Zhou (ORCID: https://orcid.org/0000-0002-2341-6338)
- Cai Shouliang
- Baoku Xu
- Jiandong Wang (ORCID: https://orcid.org/0009-0007-5365-2087)
- Yu Zhang (ORCID: https://orcid.org/0000-0002-6886-7300)
- Zitong Yang
- Liling Zhu
- Jian Cui
- Yifan Cai (ORCID: https://orcid.org/0000-0002-0407-1581)
Institutions
- Qingdao University (CN)
- Sun Yat-sen University (CN)
- Beijing University of Chinese Medicine (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Peking University (CN)
- Chinese PLA General Hospital (CN)
- Ansteel (China) (CN)
- Sun Yat-sen Memorial Hospital (CN)
- Affiliated Hospital of Qingdao University (CN)
- Peking University First Hospital (CN)
- Second Affiliated Hospital of Xi'an Jiaotong University (CN)
- Anshan Hospital (CN)
Publication Details
- Journal
- Science Advances
- Published
- 2026-09-25
- DOI
- https://doi.org/10.1126/sciadv.aeg7722
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00