Gpx1 induces M2 polarization of macrophages, contributing to doxorubicin resistance in triple-negative breast cancer

  • Hum Immunol. 2025 Aug 19;86(5):111566. doi: 10.1016/j.humimm.2025.111566.
Limu Wen  1 ,  Lijuan Lyu  2 ,  Weizhu Wu  1 ,  Yingnan Wang  3 ,  Bitao Ding  4 ,  Zhijun Dai  5
Affiliations
  • 1. Department of Thyroid and Breast Surgery, Ningbo Medical Center Lihuili Hospital, China.
  • 2. Department of Oncology, The 2nd Affiliated Hospital of Xi'an Jiaotong University, China.
  • 3. Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, China.
  • 4. Department of General Surgery, Cixi Integrated Traditional Chinese and Western Medicine Healthcare Group, China.
  • 5. Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, China. Electronic address: [email protected].
PMID: 40834701 DOI: 10.1016/j.humimm.2025.111566
Abstract

Background: Treatment failure in triple-negative breast Cancer (TNBC) primarily stems from chemotherapy resistance. Doxorubicin (DOX) is a commonly used therapeutic agent for TNBC; however, the role and mechanisms of immune regulation in DOX resistance remain unclear.

Methods: In this study, we analyzed single-cell data from public databases comparing DOX-resistant and sensitive TNBC patients, focusing on cell subpopulations, enriched pathways, and cell communication. We then explored the expression of Glutathione Peroxidase 1 (Gpx1) in macrophages and its impact on their polarization. Subsequently, we established co-culture systems of M0 macrophages and DOX-resistant TNBC cells to elucidate the specific effects of Gpx1-induced M2 polarization on the cancerous characteristics of TNBC. A xenograft nude mouse model was constructed to investigate the effect of Gpx1 expression on the sensitivity of TNBC to DOX.

Results: Our findings indicated a significant increase in macrophage proportion within TNBC DOX patient samples, with high expression of Gpx1 in the Macrophage_Gpx1+ cells of the DOX-resistant group. Enrichment analysis revealed that Gpx1 was primarily associated with immune response-related pathways, and strong interactions between Macrophage_Gpx1+ cells and Other immune cells were observed. In vitro experiments confirmed that Gpx1 induced M2 polarization of macrophages, enhancing the proliferation, migration, and invasion capabilities of DOX-resistant TNBC cells. Animal experiments revealed that knocking down Gpx1 suppressed macrophage M2 polarization and enhanced the sensitivity of TNBC to DOX.

Conclusion: This study unveiled a novel avenue for immune regulation in TNBC during DOX treatment. Inhibiting Gpx1 expression to prevent macrophage polarization towards the M2 phenotype may enhance the sensitivity of TNBC to DOX.

Keywords
Doxorubicin; Gpx1; Immunity; Macrophages; Triple-negative breast cancer.
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