Cytokine. 2026 Mar 27;202:157139. doi: 10.1016/j.cyto.2026.157139. Online ahead of print.
ABSTRACT
BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, characterized by a lack of targeted therapies and poor prognosis. The tumor microenvironment (TME) plays a pivotal role in TNBC progression, with immune mediators such as cytokines, chemokines, growth factors, and immune checkpoints driving inflammation, angiogenesis, and immune evasion.
METHODS: We conducted a comparative analysis of 81 immune-related proteins in serum samples from 137 participants: 49 healthy controls (HC), 63 non-TNBC (NTNBC) patients, and 25 TNBC patients. Protein expression was quantified using multiplex immunoassays (ProcartaPlex and MILLIPLEX MAP® panels). Statistical analyses included principal component analysis (PCA), hierarchical clustering, receive operating curves (ROC), and pathway enrichment to identify diagnostic biomarkers and molecular networks associated with TNBC aggressiveness. Ou results revealed distinct immune dysregulation in TNBC, characterized by significant overexpression of pro-inflammatory cytokines (IFN-γ, IL-12p70, IL-8), chemokines (MIP-1α, Fractalkine), growth factors (VEGF-A, SCF), and immune checkpoints (LAG-3, PD-L1). ROC curve analyses identified LAG-3, Fractalkine, and VEGF-A as the top biomarkers distinguishing healthy controls from TNBC, while IL-5, IL-27, and TNF-β effectively discriminated TNBC from NTNBC. Cytokine network analysis highlighted TSLP, IL-12p70, and IL-17 A as central hubs coordinating Th1/Th17 inflammatory responses, stromal remodeling, and immune evasion, with strong interactions between IL-17 A-ENA-78-SCF and IL-3-IL-21 axes driving TNBC aggressiveness. Stratified analyses further demonstrated stage, grade, and metastasis revealed that IL-12p70, MIP-1α, and IL-18 were elevated in late-stage TNBC; IL-17 A, IL-5, and TWEAK were significantly overexpressed in high-grade tumors; and IFN-γ, IL-8, CTLA-4 and TSLP peaked in metastatic TNBC.
CONCLUSION: Our findings identify immune mediator panels as promising diagnostic and prognostic biomarkers for TNBC.
PMID:41904922 | DOI:10.1016/j.cyto.2026.157139
