The role of tumor microenvironment and immune cell crosstalk in triple-negative breast cancer (TNBC): Emerging therapeutic opportunities.

Journal: Cancer letters
Published Date: Jun 15, 2025

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by its lack of estrogen, progesterone, and HER2 receptors, leading to limited treatment options and poor prognosis. This review synthesizes current research on the tumor microenvironment (TME) and immune cell crosstalk in TNBC to identify emerging therapeutic opportunities. The TME in TNBC is a complex ecosystem comprising immune cells, fibroblasts, and extracellular matrix components, which significantly influence tumor growth and metastasis. Single-cell RNA sequencing reveals T-cell heterogeneity and identifies prognostic genes. Regulatory T cells (Tregs) play a key role in immunosuppression, with thymidine kinase-1 (TK1) identified as a potential therapeutic target. MUC1-C and CXCL9 modulate the TME, impacting T-cell depletion and macrophage differentiation. Spatial analysis highlights the importance of cell-to-cell interactions in predicting recurrence. Epithelial-mesenchymal transition (EMT) and thermogenesis also influence the TME, while epigenetic modifications, such as HDAC inhibition, can induce pyroptosis and enhance immune cell recruitment. Integrating genomic information with TME analysis is crucial for developing personalized treatments, considering racial disparities in immune infiltration. Emerging therapies targeting immune checkpoints, modulating Treg activity, and inducing pyroptosis hold promise for improving TNBC patient outcomes. Future research should focus on multi-omics data, spatial transcriptomics, and patient-derived models to refine therapeutic interventions.

Authors

  • Hussein Sabit
    Department of Medical Biotechnology, College of Biotechnology, Misr University for Science and Technology, P.O. Box 77, Giza, 3237101, Egypt. Electronic address: hussein.sabit@must.edu.eg.
  • Amro Adel
    Department of Pharmaceutical Biotechnology, College of Biotechnology, Misr University for Science and Technology, P.O. Box 77, Giza, 3237101, Egypt.
  • Mariam M Abdelfattah
    Department of Environmental Biotechnology, College of Biotechnology, Misr University for Science and Technology, P.O. Box 77, Giza, 3237101, Egypt.
  • Rehab M Ramadan
    Department of Pharmaceutical Biotechnology, College of Biotechnology, Misr University for Science and Technology, P.O. Box 77, Giza, 3237101, Egypt.
  • Mahmoud Nazih
    Al Ryada University for Science and Technology (RST), ElMehwar ElMarkazy-2, Cairo - Alex desert RD K92, Sadat City, 16504, Egypt; Scientific Office, Egyptian Society of Pharmacogenomics and Personalized Medicine (ESPM), Cairo, Egypt.
  • Shaimaa Abdel-Ghany
    Department of Environmental Biotechnology, College of Biotechnology, Misr University for Science and Technology, P.O. Box 77, Giza, 3237101, Egypt.
  • Ahmed El-Hashash
    Elizabeth City State campus of the University of North Carolina (UNC), NC, 27909, USA.
  • Borros Arneth
    Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Hospital of the Universities of Giessen and Marburg (UKGM), Philipps University Marburg, Baldingerstr. 1, Marburg, 35043, Germany; Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Hospital of the Universities of Giessen and Marburg (UKGM), Justus Liebig University Giessen, Feulgenstr 12, Giessen, 35392, Germany. Electronic address: borros.arneth@staff.uni-marburg.de.

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