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

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..