Work

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

Year: 2025

Type: article

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.

Source: Human Immunology

DOI: 10.1016/j.humimm.2025.111566

Authors: Limu Wen, Lijuan Lyu, Weizhu Wu, Yingnan Wang, Bitao Ding, Zhijun Dai