# Siglec-15 promotes a feed-forward loop between TNBC cells and macrophages via the NF-κB/DcR3/CCL18/STAT3 axis

Article · Wang S, Wang HQ, Zhao H, Zhao R, Zhao P, Mu Q

- Archive id: doi:10.1016/j.tranon.2026.103032
- Published: 2026-09-18
- Venue: Translational oncology
- DOI: https://doi.org/10.1016/j.tranon.2026.103032
- PMID: 42759405
- PMCID: PMC13625897
- Citations: 0
- Source URL: https://doi.org/10.1016/j.tranon.2026.103032
- PDF: https://europepmc.org/articles/PMC13625897/pdf
- Provenance: europepmc

## Abstract

M2-like tumor-associated macrophages (TAMs), recognized as a significant risk factor in tumor progression, play a crucial role in the tumor microenvironment. While Sialic acid binding Ig like Lectin 15 (Siglec-15), an well-characterized immune-checkpoint inhibitor, has been demonstrated to impact immunotherapy response and tumor progression, its role in TMAs-mediated tumor progression remains largely unclear. In this study, we demonstrated that the high expression of Siglec-15 in triple-negative breast cancer (TNBC) acts as a pivotal driver of the interaction between tumor cells and macrophages. TNBC cells with overexpressed Siglec-15 can induce the polarization of macrophages into CC chemokine ligand 18 (CCL18) + M2 macrophages and recruit macrophages. Furthermore, CCL18⁺ M2 TAMs can directly facilitate the malignant behaviors of TNBC cells. Mechanistically, they secrete CCL18, which promotes the expression of Siglec-15 via the phosphorylation of signal transducer and activator of transcription 3 (STAT3), thereby indirectly accelerating tumor progression. Molecular biochemical assays, including RNA sequencing on TNBC cells with overexpressed Siglec-15 and capillary reverse-phase liquid chromatography (LC)-tandem mass spectrometry (MS/MS) of the cell supernatant, demonstrated Siglec-15 upregulated the expression of Decoy receptor 3 (DcR3) in macrophages through Nuclear factor-kappa B (NF-κB) pathway. In summary, this study reveals a novel Siglec-15-mediated positive feed-forward loop between TNBC cells and macrophages, which relies on the NF-κB/DcR3/CCL18/STAT3 signaling axis to facilitate TNBC progression..

_Abstract reproduced under CC-BY (article license as recorded by Europe PMC; abstract reproduced unmodified apart from markup removal)._

Topics: [Cancer Immunotherapy](https://space-kitty.com/topics/cancer-immunotherapy)

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