2. Academic Validation
  3. M1 macrophages enhance breast cancer chemoresistance via JAK-STAT3 signaling

M1 macrophages enhance breast cancer chemoresistance via JAK-STAT3 signaling

  • Biochim Biophys Acta Mol Basis Dis. 2025 Sep 18;1872(1):168056. doi: 10.1016/j.bbadis.2025.168056.
Yining Feng 1,  Fei Chen 1,  Chenglong Mu 2,  Luqi Wang 1,  Yuhan Jiang 3,  Dan Liu 2,  Dameng Li 2,  Chen Liang 2,  Yanhua Zhai 2,  Tao Yang 2,  Alan Wells 4,  Amanda M Clark 5,  Liang Wei 6,  Bo Ma 7
Affiliations

Affiliations

  • 1 Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
  • 2 Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China.
  • 3 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing 100730, China.
  • 4 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, 15260, USA; Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15260, USA; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA; VA Pittsburgh Healthcare System, Pittsburgh, PA, 15213, USA.
  • 5 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, 15260, USA; UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA; VA Pittsburgh Healthcare System, Pittsburgh, PA, 15213, USA. Electronic address: AMC235@pitt.edu.
  • 6 Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. Electronic address: weiliang@xzhmu.edu.cn.
  • 7 Cancer Institute, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China; Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, 99 West Huaihai Road, Xuzhou, 221002, Jiangsu, China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China. Electronic address: boma@xzhmu.edu.cn.
PMID: 40975142 DOI: 10.1016/j.bbadis.2025.168056
Abstract

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, playing a key role in breast Cancer (BrCa) progression and chemotherapy response. While TAMs exhibit diverse phenotypes, the M1/M2 classification remains widely used. M1-like macrophages are known for tumor-killing properties, whereas M2-like macrophages promote tumor growth. However, the impact of TAM subtypes on chemotherapy response remains inconsistent. In this study, we found that M1-like macrophages or their conditioned medium (CM) induced greater BrCa cell death and inhibited proliferation compared to M2-like macrophages. Surprisingly, BrCa cells surviving M1-like macrophage-induced killing displayed increased chemotherapy resistance, independent of proliferation. Transcriptomic profiling indicated upregulation of the JAK-STAT signaling pathway, with elevated STAT3 phosphorylation subsequently confirmed at the protein level. Inhibition of JAKs with Ruxolitinib reduced STAT3 activation and restored chemotherapy sensitivity. Our findings highlight the dual role of M1-like macrophages, demonstrating both tumoricidal activity and the potential to induce chemotherapy resistance in surviving tumor cells, offering insights for macrophage-targeted therapies.

Keywords

Breast cancer; Chemoresistance; M1-like macrophages; M2-like macrophages.

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