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  3. Single-cell transcriptome analysis reveals the malignant characteristics of tumour cells and the immunosuppressive landscape in HER2-positive inflammatory breast cancer

Single-cell transcriptome analysis reveals the malignant characteristics of tumour cells and the immunosuppressive landscape in HER2-positive inflammatory breast cancer

  • J Exp Clin Cancer Res. 2025 Jul 8;44(1):196. doi: 10.1186/s13046-025-03454-z.
Juan Huang # 1 2 3 4,  Yongwei Zhu # 5,  Wenjing Zeng 1,  Yulong Zhang 6,  Weizhi Xia 7,  Fan Xia 1 2 3,  Liyu Liu 4 8 9,  Kuansong Wang 10,  Yidi Guan 4 8 10,  Taohong Shen 11,  Bingjian Jiang 12,  Lunquan Sun 4 8 9,  Ayong Cao 13,  Shouman Wang 14 15 16,  Zhi Li 17 18 19
Affiliations

Affiliations

  • 1 Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, China.
  • 2 Multidisciplinary Breast Cancer Center, Xiangya Hospital, Central South University, Changsha, China.
  • 3 Clinical Research Center For Breast Cancer In Hunan Province, Xiangya Hospital, Central South University, Changsha, China.
  • 4 Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China.
  • 5 Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
  • 6 Department of Respiratory, The Sixth Clinical Medical College of Xinjiang Medical University, Urumqi, China.
  • 7 The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China.
  • 8 Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China.
  • 9 Institute of Cancer Research, National Clinical Research Center for Geriatric Disorders (Xiangya), Xiangya Hospital, Central South University, Changsha, China.
  • 10 Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
  • 11 Huarong County People's Hospital, Hunan, China.
  • 12 Department of Breast and Thyroid Surgery, The People's Hospital of Xiangxi Autonomous Prefecture, Jishou, Hunan, China.
  • 13 Key Laboratory of Breast Cancer, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. caoayong0309@sina.com.
  • 14 Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha, China. wangshouman@126.com.
  • 15 Multidisciplinary Breast Cancer Center, Xiangya Hospital, Central South University, Changsha, China. wangshouman@126.com.
  • 16 Clinical Research Center For Breast Cancer In Hunan Province, Xiangya Hospital, Central South University, Changsha, China. wangshouman@126.com.
  • 17 Xiangya Cancer Center, Xiangya Hospital, Central South University, Changsha, China. peries@csu.edu.cn.
  • 18 Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha, China. peries@csu.edu.cn.
  • 19 Institute of Cancer Research, National Clinical Research Center for Geriatric Disorders (Xiangya), Xiangya Hospital, Central South University, Changsha, China. peries@csu.edu.cn.
  • # Contributed equally.
PMID: 40624675 DOI: 10.1186/s13046-025-03454-z
Abstract

Background: Inflammatory breast Cancer (IBC), of which HER2 + is the predominant subtype, is extremely aggressive and difficult to treat. Previous studies have suggested that targeting the tumour microenvironment (TME) may provide new directions for IBC diagnosis and treatment.

Methods: In this study, we used single-cell transcriptome technology (scRNA-seq) to investigate the molecular features of the TME of HER2 + IBC patients and performed a comprehensive and detailed comparison of the cellular components and molecular phenotypes of the TME between IBC patients and noninflammatory breast Cancer (nIBC) patients to elucidate the cell types that are specifically enriched in the TME of IBC patients, as well as the molecular features that are responsible for the preferential remodelling of the cellular functional state in the TME.

Results: A total of 15,832 cells, including epithelial cells, endothelial cells, stromal cells, T cells, B cells, antibody secreting cells (ASCs) and myeloid cells, were obtained from tumour tissues from 3 HER2 + IBC patients for scRNA analysis. By comparing the TME with that of HER2 + nIBC patients in a public database, we found that the TME of HER2 + IBC patients had a greater level of lymphocyte infiltration than that of nIBC patients did, and an especially significant enrichment of ASCs (mainly plasmablasts or plasma cells). In the TME of HER2 + IBC patients, tumour-infiltrating T cells exhibited a dual molecular phenotype of high activation and high exhaustion, with tumour-infiltrating B cells preferring the extrafollicular developmental pathway, and tumour-infiltrating myeloid and mesenchymal cells exhibiting a greater immunosuppressive status. By performing a cellular interaction analysis, we revealed that PTN molecules were significantly overexpressed in HER2 + IBC tumour cells and that the cellular interactions mediated by these molecules were strongly correlated with the functional polarisation of the cellular components in the TME. We observed that HER2 + IBC tumour cells have an active interferon response and epithelial mesenchymal transition (EMT) signalling, and that their malignant process is strongly correlated with the inflammatory response. Moreover, we found that HER2 + IBC tumour-infiltrating B cells promoted Necroptosis of endothelial cells through high expression of TNF, thus promoting inflammatory responses.

Conclusion: We found a strong correlation between high expression of PTN molecules in HER2 + IBC tumour cells and their highly invasive characteristics and highly immunosuppressive TME. These results suggest that HER2 + IBC tumour cells can promote an inflammatory response by upregulating the expression of TNF molecules in B cells via PTN molecules and that the enhanced inflammatory response in turn promotes tumour progression, a malignant cycle that shapes a more immunosuppressive TME. Therefore, diagnostic and therapeutic strategies targeting the PTN-TNF molecular axis may have considerable potential for development in HER2 + IBC patients.

Keywords

HER2; IBC; Immunosuppression; PTN; ScRNA; TME; TNF.

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