review · Cancer Letters
Triple-negative breast cancer lacks common hormonal and HER2 receptors, resulting in restricted therapeutic choices and poor clinical prognosis. Interactions within the tumour microenvironment, which contains immune cells, fibroblasts, and extracellular matrix, strongly drive tumour expansion and metastasis. Single-cell RNA sequencing reveals T-cell diversity and flags prognostic genes, whilst regulatory T cells facilitate immunosuppression, identifying thymidine kinase-1 as a potential therapeutic target. Regulators such as MUC1-C and CXCL9 alter the local environment by influencing T-cell depletion and macrophage differentiation, and spatial cell arrangements help predict cancer recurrence. Furthermore, epithelial-mesenchymal transition and epigenetic alterations, including histone deacetylase inhibition, induce pyroptosis and recruit immune cells. Combining genomic data with microenvironment analysis, whilst addressing racial variations in immune infiltration, informs emerging approaches such as immune checkpoint targeting.
Triple-negative breast cancer is difficult to treat because it lacks standard therapeutic receptors. Understanding how cancer cells interact with the surrounding immune system uncovers critical vulnerabilities. This knowledge guides the design of tailored interventions, which could improve survival outcomes by reversing the mechanisms tumours use to evade immune detection.
The insights support early-stage drug discovery and diagnostic development for biotechnology and pharmaceutical developers. Identified targets such as thymidine kinase-1, combined with checkpoint modulators and histone deacetylase inhibitors, suggest avenues for targeted therapeutics and recurrence-predicting spatial assays. As the work synthesises mechanistic evidence and calls for patient-derived models and spatial transcriptomics, the clinical applications currently remain at an early, preclinical research stage.
AI-generated from the published abstract. Always read the original work before citing.
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.
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DOI: 10.1016/j.canlet.2025.217865
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