ArticleCancer letters2025
TRAIL induces cytokine production via the NFkB2 pathway promoting neutrophil chemotaxis and neutrophil-mediated immune-suppression in triple negative breast cancer cells.
Article in Cancer letters, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Synergistic lethality of combination treatment with Trop2-directed antibody-drug conjugate sacituzumab govitecan and TRAIL agonists in triple negative breast cancer.Breast cancer research : BCR · 2026Article
- ChEA-KG and ChEA-KG-TS: a network-based transcription factor enrichment analysis tool with an accompanying time-series workflow.Nucleic acids research · 2026Article
- S100A14 promotes colorectal cancer progression and anti-PD-1 resistance via UPF1-mediated activation of the non-canonical NF-κB signaling.Cell death & disease · 2026Article
- PLK1 stabilizes β-catenin to drive colorectal carcinogenesis through NFKB2-mediated transcriptional activation of USP2a and site-specific phosphorylation.Theranostics · 2026Article
- The chemokine network in triple-negative breast cancer: its role in immune microenvironment regulation, and prospects for targeted therapy.Frontiers in immunology · 2026Review
- Modulating N1 and N2 neutrophils in breast cancer: potential therapeutic approaches - a narrative review.Annals of medicine and surgery (2012) · 2026Review
- Decoding the functional roles of circular RNAs linked to NF-κB pathway in carcinogenesis.Discover oncology · 2025Review
- Roles of Neutrophils in Autoimmune Diseases and Cancers.International journal of molecular sciences · 2025Review
- Neoantigen-Driven Immunotherapy in Triple-Negative Breast Cancer: Emerging Strategies and Clinical Potential.Biomedicines · 2025Review
- Neutrophil Dynamics in Response to Cancer Therapies.Cancers · 2025Review
- Combination of LowDose Epigenetic Modifiers and TIC10 for the Activation of Antitumor Immunity and Inhibition of Tumor Growth in Gastrointestinal Cancer.Cancer medicine · 2025Article
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Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic that induces apoptosis in cancer cells while sparing the non-malignant cells in preclinical models. However, its efficacy in clinical trials has been limited, suggesting unknown mechanisms modulating TRAIL activity in patients. We hypothesized that TRAIL treatment elicits transcriptional changes in triple negative breast cancer (TNBC) cells that alter the immune milieu. RNAseq analysis of MDA-MB-231 cells along with validation in additional cell lines demonstrated that TRAIL induced cytokines such as CXCLs 1, 2, 3, 8,11 and IL-6, which are known to modify neutrophil function. Mechanistically, TRAIL dependent induction of the cytokines was predominantly mediated by death receptor 5, caspase-8 and the non-canonical NFKB2 pathway. These cytokines produced by TRAIL-treated TNBC cells enhanced chemotaxis of normal human donor isolated neutrophils. Using TNBC xenograft models, TRAIL induced activation of NFkB2 pathway, cytokine production and increased neutrophil recruitment into the tumors. Moreover, preincubation of neutrophils in supernatants from TRAIL-treated TNBC cells significantly impaired neutrophil function as measured by reduced respiratory burst and cytotoxic effect against TNBC cells. Transcriptomic analysis of neutrophils incubated with either TRAIL alone or supernatant of TRAIL-treated TNBC cells revealed increased expression of inflammatory cytokines, immune modulatory genes, immune checkpoint genes, and genes implicated in delayed neutrophil apoptosis. Functional studies showed that these neutrophils suppress T cell proliferation and augment Treg suppressive phenotype. Collectively, our study demonstrates a novel role of TRAIL-induced NFKB2-dependent cytokine production that promotes neutrophil chemotaxis and neutrophil-mediated immune suppression.
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