Affinage

SIGLEC15

Sialic acid-binding Ig-like lectin 15 · UniProt Q6ZMC9

Length
328 aa
Mass
35.7 kDa
Annotated
2026-04-28
80 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Siglec-15 is a conserved sialic acid-binding immunoglobulin-like lectin that couples glycan recognition to intracellular signaling through the DAP12/Syk axis, functioning as a critical regulator of both osteoclast differentiation and immune suppression. In osteoclasts, Siglec-15 associates via its transmembrane lysine with DAP12 to activate PI3K/Akt, Erk, and RAP1/Rac1 pathways (through a p130CAS/CrkII complex), driving NFATc1-dependent differentiation, actin ring formation, and bone resorption; Siglec-15-deficient mice exhibit osteopetrosis and resistance to estrogen-deficiency-induced bone loss (PMID:22451653, PMID:23677868, PMID:25460183, PMID:38849345). Siglec-15 recognizes α2,3- and α2,6-linked sialoglycans on counter-receptors including LRP1 and CD11b, and its surface stability and immunosuppressive activity depend on N-glycosylation at N172 (PMID:37311743, PMID:41569849, PMID:34094685). In the tumor microenvironment, Siglec-15 expressed on macrophages and tumor cells suppresses CD8+ T cell responses—in a manner mutually exclusive with PD-L1—by engaging sialylated ligands such as TLR2 and CD11b, and promotes M2-like macrophage polarization via SYK/MAPK signaling; genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity across multiple tumor models (PMID:30833750, PMID:35077803, PMID:37607544).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2007 High

    Identifying Siglec-15 as a DAP12/DAP10-associated sialic acid-binding receptor with sialyl-Tn preference established it as a potential activating signaling lectin, resolving the question of whether this orphan Siglec had signaling capacity.

    Evidence Recombinant protein binding assays and co-immunoprecipitation with transmembrane domain analysis

    PMID:17483134

    Open questions at the time
    • Physiological ligands on cells unknown
    • Downstream signaling pathways not mapped
    • In vivo function uncharacterized
  2. 2012 High

    Demonstrating that Siglec-15 signals through a DAP12-Syk complex to drive osteoclast formation and TGF-β secretion upon tumor sialyl-Tn recognition established dual roles in bone biology and tumor-immune crosstalk, answering what the DAP12 coupling achieves functionally.

    Evidence siRNA knockdown, K272A/K274A mutagenesis, Syk inhibitor treatment, bone resorption assay, and co-culture TGF-β ELISA

    PMID:22451653 PMID:23035012

    Open questions at the time
    • In vivo skeletal phenotype not yet established
    • Whether TGF-β induction is reproducible across labs (later contested)
    • Downstream transcriptional targets unresolved
  3. 2013 High

    Generation of Siglec-15 knockout mice revealed mild osteopetrosis and impaired PI3K/Akt and Erk signaling, establishing Siglec-15 as a non-redundant co-stimulatory receptor for osteoclast differentiation in vivo while showing that OSCAR/FcRγ can partially compensate.

    Evidence Siglec-15 KO mice with histomorphometry, retroviral rescue of mutants, Western blot for PI3K/Akt/Erk

    PMID:23677868

    Open questions at the time
    • Role in pathological bone loss models untested
    • Mechanism of cytoskeletal defects unclear
    • Compensatory pathways not fully defined
  4. 2014 High

    Showing that Siglec-15-null mice resist ovariectomy-induced bone loss and that anti-Siglec-15 antibodies increase bone density by inducing receptor internalization and degradation established Siglec-15 as a therapeutic target for osteoporosis.

    Evidence Ovariectomy model in KO mice, monoclonal antibody-induced internalization/degradation, DXA bone density measurement

    PMID:24446437 PMID:25460183

    Open questions at the time
    • Antibody mechanism of action in immune cells unknown
    • Whether surface removal affects immune functions untested
    • Cytoskeletal signaling intermediates unidentified
  5. 2019 High

    A genome-scale T cell activity screen identified Siglec-15 as a major immune suppressor mutually exclusive with PD-L1, fundamentally expanding its biology from bone to cancer immunology and answering whether Siglec-15 has non-redundant immunoregulatory function.

    Evidence Genome-scale screen, in vitro T cell suppression, genetic ablation and antibody blockade in mouse tumor models

    PMID:30833750

    Open questions at the time
    • Receptor on T cells not identified
    • Molecular mechanism of T cell suppression unknown
    • Relevance to human clinical responses unproven
  6. 2019 Medium

    Linking a SIGLEC15 polymorphism to recurrent vulvovaginal candidiasis revealed a role in mucosal antifungal immunity beyond bone and cancer, showing that Siglec-15 regulates inflammatory cytokine responses and fungal clearance.

    Evidence GWAS integration, PBMC stimulation, in vivo siRNA silencing in mouse vaginal infection model

    PMID:31189718

    Open questions at the time
    • Precise ligand on Candida or host cells at mucosal surface unknown
    • Mechanism connecting Siglec-15 to NLRP3/IL-1β not established
    • Not replicated in independent cohorts
  7. 2021 High

    Broadening glycan specificity from sialyl-Tn alone to general α2,3- and α2,6-sialoglycans, and showing that N-glycosylation at N172 is required for protein stability and immunosuppressive function, resolved the ligand selectivity question and identified a key post-translational regulatory mechanism.

    Evidence Glycan microarray, site-directed mutagenesis (N172Q), tumor models in immunocompetent vs. nude mice, glycosidase treatment

    PMID:32501471 PMID:32921411 PMID:34094685

    Open questions at the time
    • Structural basis for glycan selectivity not resolved at atomic level
    • Glycosylation-dependent interactome changes uncharacterized
    • TGF-β secretion finding from 2012 could not be reproduced
  8. 2022 High

    Demonstrating that Siglec-15 on tumor-associated macrophages engages α2,3-sialylated PDAC cells to activate SYK and drive M2-like polarization established the immunosuppressive signaling axis in solid tumors and showed it is pharmacologically reversible with SYK inhibitors.

    Evidence Co-culture with SYK phosphorylation readout, sialic acid binding assay, SYK inhibitor treatment in vivo

    PMID:35077803

    Open questions at the time
    • Specific sialylated glycoprotein counter-receptor on tumor cells not identified in this context
    • Whether SYK inhibition affects bone-side Siglec-15 function simultaneously
    • Human TAM relevance limited to correlative data
  9. 2023 High

    Crystal structure determination and identification of CD11b and sialylated TLR2 as functional binding partners on T cells and osteoclast-derived apoptotic bodies, respectively, answered what the molecular targets of Siglec-15 are on immune cells and revealed the structural basis for antibody blockade.

    Evidence X-ray crystallography, STD-NMR, molecular dynamics, Co-IP for CD11b and TLR2, T cell binding assays, neutralizing antibody in bone metastasis model

    PMID:37311743 PMID:37607544

    Open questions at the time
    • Whether CD11b and TLR2 binding are mutually exclusive or cooperative unknown
    • How Siglec-15 engagement of CD11b mechanistically suppresses T cell activation not detailed
    • Relative contributions of different counter-receptors in vivo unquantified
  10. 2023 Medium

    Identification of ETS-1/ETS-2 downstream of TGF-β/ERK and NFκB as transcriptional drivers of SIGLEC15, and Arid1a/Jun-Fos chromatin remodeling as an epigenetic regulator, established how Siglec-15 expression is controlled in disease contexts.

    Evidence ChIP for ETS-1/ETS-2 and Jun/Fos at SIGLEC15 promoter, ATAC-seq, NFκB inhibition, luciferase reporters, conditional Arid1a KO

    PMID:36614238 PMID:37465593 PMID:38477755

    Open questions at the time
    • Integration of NFκB vs. ETS-1/2 vs. Arid1a regulatory inputs unclear
    • Whether these transcriptional mechanisms operate in immune cells vs. tumor cells specifically
    • Post-transcriptional regulation (e.g., miR-7109-3p axis) not connected to chromatin-level control
  11. 2024 High

    A genome-wide CRISPR screen identified LRP1 as a direct Siglec-15 counter-receptor on osteoclast precursors and St3gal4 as the glycosyltransferase generating its α2,3-sialylated ligand, while biochemical work revealed Siglec-15 activates RAP1/Rac1 via a p130CAS/CrkII complex for actin ring formation; Siglec-15/FcRγ double KO causes severe osteopetrosis.

    Evidence Genome-wide CRISPR KO screen, Siglec-15 binding validation, Co-IP of p130CAS/CrkII, double KO mice with bone analysis

    PMID:38849345 PMID:41569849

    Open questions at the time
    • Whether LRP1 is also a Siglec-15 counter-receptor in the immune context
    • Structural basis for Siglec-15/LRP1 interaction unresolved
    • How p130CAS/CrkII complex is recruited to the DAP12/Syk axis not fully delineated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include how Siglec-15 engagement of distinct counter-receptors (LRP1, CD11b, TLR2) leads to context-specific outcomes in bone vs. immune cells, what determines the switch between DAP12-Syk and alternative downstream pathways, and whether Siglec-15 blockade will prove effective in human cancer immunotherapy.
  • No human clinical efficacy data for anti-Siglec-15 therapy reported in the timeline
  • Context-specific signaling downstream of different counter-receptors not compared systematically
  • Relative contribution of soluble vs. membrane-bound Siglec-15 in immunosuppression unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 2
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-162582 Signal Transduction 5 R-HSA-168256 Immune System 5
Partners
CD11BCD44DAP10DAP12EGFRLRP1SYKTLR2
Complex memberships
Siglec-15/DAP12/SykSiglec-15/p130CAS/CrkII

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Siglec-15 is a type-I transmembrane protein with two Ig-like domains that preferentially recognizes the Neu5Acα2-6GalNAcα- (sialyl-Tn) structure and associates with activating adaptor proteins DAP12 and DAP10 via a lysine residue in its transmembrane domain, implying activating signaling function. Recombinant protein binding assays, co-immunoprecipitation, domain analysis Glycobiology High 17483134
2011 Siglec-15 mRNA and protein increase during osteoclast differentiation stimulated by RANKL or TNF-α, and antibody blockade of Siglec-15 markedly inhibits osteoclast differentiation in primary mouse bone marrow macrophages and human osteoclast precursors. In vitro osteoclast differentiation assay with polyclonal antibody blockade, TRAP staining Biochemical and biophysical research communications Medium 21586272
2012 Siglec-15 is expressed on tumor-associated macrophages and, upon recognition of sialyl-Tn (sTn) antigen on tumor cells, transduces a signal through DAP12 to Syk kinase, leading to enhanced TGF-β secretion from monocytes/macrophages; this requires the DAP12-binding lysine (Lys274) in the transmembrane domain, and is blocked by Syk inhibitors or K274A mutation. Co-culture model, Syk inhibitor treatment, site-directed mutagenesis (K274A), ELISA for TGF-β Glycobiology High 23035012
2012 Siglec-15 is NFAT2/NFATc1-inducible in osteoclasts and links RANKL-RANK-NFAT2 signaling to DAP12; both sialylated glycan recognition by the V-set domain and association with DAP12 via Lys-272 are essential for functional osteoclast formation. Siglec-15 knockdown reduces multinucleated cell formation and bone resorption. Siglec-15 forms complexes with Syk through DAP12 in response to vitronectin. siRNA knockdown, retroviral transduction of mutants (K272A), bone resorption assay, Co-IP (Siglec-15/DAP12/Syk complex) The Journal of biological chemistry High 22451653
2013 Siglec-15 regulates osteoclast development by modulating RANKL-induced PI3K/Akt and Erk signaling pathways in association with DAP12. Siglec-15-deficient mice show mild osteopetrosis due to impaired osteoclast development. The association of Siglec-15 with DAP12 is required for downstream RANK signal transduction, and OSCAR/FcRγ signaling can compensate for Siglec-15 loss in the primary spongiosa. Siglec-15 knockout mice, retroviral transduction of wild-type and mutant Siglec-15, Western blotting for PI3K/Akt and Erk, histomorphometry, in vitro osteoclast assays Journal of bone and mineral research High 23677868
2014 Siglec-15 is localized to the plasma membrane where it interacts with DAP12 and induces Akt activation when clustered on the osteoclast cell surface. Monoclonal antibodies targeting Siglec-15 induce rapid internalization, lysosomal targeting, and degradation of Siglec-15 via receptor dimerization, and antibody treatment increases bone mineral density in mice. Monoclonal antibody treatment, in vitro osteoclast differentiation assay, mouse bone density measurement (DXA), Western blot for Akt activation, immunofluorescence for localization/internalization The Journal of biological chemistry High 24446437
2014 Siglec-15-deficient mice are resistant to estrogen deficiency-induced bone loss after ovariectomy. Siglec-15-null osteoclasts are small and fail to spread on bone surfaces, indicating impaired cytoskeletal organization. The Siglec-15/DAP12 pathway is specifically important for cytoskeletal organization in both RANKL- and TNF-α-induced osteoclastogenesis. Ovariectomy mouse model with Siglec-15 KO mice, histomorphometry, in vitro osteoclast assays, TRAP staining Bone High 25460183
2015 Siglec-15 mediates periarticular bone loss but not joint destruction or cartilage damage in antigen-induced arthritis. Siglec-15-deficient mice show significantly lower periarticular bone loss with impaired mature multinucleated osteoclast formation in periarticular regions. Murine antigen-induced arthritis model, histological analysis, Siglec-15 KO mice Bone High 26027508
2019 Siglec-15 is a critical immune suppressor in the tumor microenvironment: it suppresses antigen-specific T cell responses in vitro and in vivo. Its expression is induced by M-CSF and downregulated by IFN-γ, and it is mutually exclusive with B7-H1/PD-L1 expression. Genetic ablation or antibody blockade of Siglec-15 amplifies anti-tumor immunity and inhibits tumor growth. Genome-scale T cell activity array, in vitro T cell suppression assays, genetic ablation, antibody blockade, mouse tumor models Nature medicine High 30833750
2019 A SIGLEC15 polymorphism associated with recurrent vulvovaginal candidiasis leads to an altered cytokine profile after Candida stimulation in PBMCs, increased IL-1B and NLRP3 expression in HeLa cells, and in vivo silencing of Siglec15 at the vaginal surface increases fungal burden while increasing polymorphonuclear leukocytes. GWAS/genomic integration, PBMC stimulation assays, in vivo siRNA silencing in mouse vaginal infection model, flow cytometry Science translational medicine Medium 31189718
2020 Siglec-15 is crucial for bone erosion in a serum-transfer arthritis model; Siglec-15 knockout mice show significantly reduced bone erosion area and osteoclast numbers in arthritic joints, while inflammation and cartilage destruction are unchanged. K/BxN serum-transfer arthritis model, Siglec-15 KO mice, histological analysis Journal of immunology High 33020147
2020 N-glycosylation of Siglec-15 stabilizes the protein by decreasing its lysosome-dependent degradation and promotes Siglec-15 transportation to the cell membrane; Siglec-15 is completely N-glycosylated in vitro and in vivo, and this is regulated by glucose uptake. Glycosidase and glycosylation inhibitor treatment, immunofluorescence for subcellular localization, Western blot for protein stability Biochemical and biophysical research communications Medium 32921411
2020 LINC00973 positively regulates Siglec-15 expression at the transcriptional level by sponging miR-7109-3p (competing endogenous RNA mechanism), thereby controlling Siglec-15 cell surface abundance and contributing to cancer immune suppression. lncRNA knockdown/overexpression, luciferase reporter assay, miRNA target validation, co-culture immune activation assay Cancer science Medium 32780490
2021 Siglec-15 promotes migration of hepatoma cells by interacting with CD44 (which is modified by α2,6-linked sialic acids on N-glycans); CD44 sialylation is required for the Siglec-15/CD44 interaction, and Siglec-15 prevents lysosomal-mediated degradation of CD44 to promote its stability. Co-immunoprecipitation, sialidase treatment, lysosomal inhibitor assay, migration assay, Western blot FEBS letters Medium 34328657
2021 Siglec-15 binds with higher avidity to α2,3- and α2,6-linked sialoglycans (not exclusively sialyl-Tn) as shown by glycan microarray; antibody cross-linking of Siglec-15 activates SYK/MAPK signaling in monocytic cells. Enhanced TGF-β secretion following co-culture with sTn-expressing tumor cells could not be reproduced. Glycan microarray, antibody cross-linking, Western blot for SYK/MAPK activation, co-culture with tumor cells Glycobiology Medium 32501471
2021 Glycosylation of Siglec-15 at N172 (N173 in mouse) is required for its immunosuppressive function; the N172Q glycosylation-deficient mutant reduced tumor growth in immunocompetent (C57BL/6) but not nude mice, indicating glycosylation is necessary for immune evasion function. Mass spectrometry, site-directed mutagenesis (N172Q), xenograft models in immunocompetent vs. nude mice American journal of cancer research High 34094685
2021 Siglec-15 promotes OS cell proliferation, migration, and invasion through activation of DUSP1 (MKP1), which mediates suppression of p38/MAPK and JNK/MAPK; Siglec-15 silencing downregulates DUSP1 and DUSP1 overexpression rescues the phenotype of Siglec-15-knockdown cells. siRNA knockdown, RNA-Seq, DUSP1 rescue overexpression, Western blot for MAPK pathways, xenograft model Frontiers in oncology Medium 34336699
2022 SIGLEC15 on tumor-associated macrophages in pancreatic cancer interacts with α-2,3-linked sialic acids on PDAC cells to stimulate SYK phosphorylation in TAMs, which promotes M2-like polarization and immunosuppressive cytokine/chemokine production. This is blocked by SYK inhibitor in vivo. Co-culture assay, Western blot for SYK phosphorylation, sialic acid binding assay, SYK inhibitor treatment in vivo, flow cytometry Cancer letters High 35077803
2022 Siglec-15 promotes M2-macrophage polarization in pancreatic cancer partly by interacting with Glut1 to upregulate glycolysis, and this regulation is also dependent on the cGAS-STING pathway; Siglec-15 knockout in macrophages reduces M2 markers (Arg1, CD206) and inhibits tumor growth in vivo. Siglec-15 KO macrophages, Co-IP (Siglec-15/Glut1), subcutaneous tumor model, Western blot, flow cytometry Oxidative medicine and cellular longevity Low 36105484
2023 Crystal structure of Siglec-15 was solved and its binding epitope determined via co-crystallization with a blocking antibody. STD-NMR and molecular dynamics reveal binding mode to α2,3- and α2,6-linked sialic acids and STn glycoform. Siglec-15 binding to T cells (which lack STn) depends on α2,3- and α2,6-linked sialoglycans, and the leukocyte integrin CD11b was identified as a Siglec-15 binding partner on human T cells. X-ray crystallography, STD-NMR, molecular dynamics simulation, Co-IP/pulldown for CD11b interaction, T cell binding assays Nature communications High 37311743
2023 Osteoclast-derived apoptotic bodies bearing Siglec-15 on their membranes bind sialylated TLR2 on naive CD8+ T cells, blocking downstream co-stimulatory signaling and inhibiting T cell activation; Siglec-15 neutralizing antibodies reduce secondary breast cancer bone metastasis. AB-null MRL/lpr mice, flow cytometry, Co-IP (Siglec-15/sialylated TLR2), T cell activation assays, neutralizing antibody treatment in vivo Cell reports. Medicine Medium 37607544
2023 Transcription factors ETS-1 and ETS-2 bind to the Siglec-15 promoter to enhance transcription in hepatocellular carcinoma cells; TGF-β1 activates the Ras/C-Raf/MEK/ERK1/2 pathway to phosphorylate ETS-1 and ETS-2, which upregulates Siglec-15 transcription. ChIP assay (ETS-1/ETS-2 promoter binding), luciferase reporter assay, TGF-β1 stimulation, ERK1/2 phosphorylation Western blot, siRNA knockdown International journal of molecular sciences Medium 36614238
2023 Siglec-15 expression in B-ALL is driven by NFκB activation, which also increases surface localization of Siglec-15. Soluble/secreted Siglec-15 circulates at elevated levels in children with B-ALL and correlates with an immunosuppressive cytokine milieu. Genetic inhibition of Siglec-15 in murine B-ALL promotes immune clearance with expanded CD8+ T cells and reduced immunosuppressive cytokines. NFκB inhibition, Western blot, flow cytometry, mouse B-ALL model with Siglec-15 KO, cytokine measurement (ELISA) Cancer research communications Medium 37465593
2023 Siglec-15 inhibits T cell activation in anaplastic thyroid cancer by reducing NFAT1, NFAT2, and NF-κB signals. Anti-Siglec-15 antibody increases IFN-γ and IL-2 secretion and enhances CD8+ T cell cytotoxicity in co-culture and in immunocompetent mouse ATC models. Anti-Siglec-15 antibody co-culture, zebrafish xenograft model, immunocompetent mouse tumor model, Western blot for NFAT/NF-κB, flow cytometry International immunopharmacology Medium 38652971
2023 Siglec-15 promotes migration of thyroid carcinoma cells by binding EGFR in a sialic acid-dependent manner and increasing EGFR protein stability; removal of sialic acid residues disrupts the Siglec-15/EGFR interaction, and EGFR pathway inhibition blocks the Siglec-15-mediated migratory effect. Pull-down assay (Siglec-15/EGFR), cycloheximide protein stability assay, sialidase treatment, wound-healing and transwell migration assay, EGFR inhibitor treatment Glycobiology Medium 37129515
2021 SIGLEC15 expression in PBMCs and mouse vaginal tissue is upregulated by Aspergillus fumigatus stimulation; SIGLEC15 silencing decreases PBMC killing capacity of A. fumigatus, indicating a role in antifungal defense. In vitro PBMC stimulation, siRNA silencing, killing assay Cell reports. Medicine Medium 34095887
2024 Siglec-15 activates M-CSF-induced RAP1/Rac1 cytoskeletal remodeling in osteoclasts through formation of a complex with p130CAS and CrkII; Siglec-15-deficient osteoclasts fail to form actin rings, and Siglec-15/FcRγ double-deficient mice develop severe osteopetrosis. Siglec-15 KO mice, Siglec-15/FcRγ double KO mice, biochemical complex analysis (co-immunoprecipitation of p130CAS/CrkII), actin ring assay, bone mass analysis Bone research High 38849345
2024 The chromatin remodeling factor Arid1a cooperates with transcription factors Jun/Fos to increase chromatin accessibility at the Siglec15 promoter, thereby upregulating Siglec15 and promoting osteoclast differentiation; BMDM-specific Arid1a KO reduces Siglec15 expression, impairs osteoclast fusion, and increases bone mass. Conditional Arid1a KO in BMDMs, ATAC-seq/chromatin accessibility assay, ChIP for Jun/Fos at Siglec15 promoter, in vivo bone phenotype analysis, ovariectomy model Journal of bone and mineral research High 38477755
2024 CA72-4 derived from synovial cells binds to Siglec-15 on macrophages (demonstrated by Co-IP) and through this interaction activates TIGIT/SHP-1 signaling to inhibit MSU-induced macrophage M1 polarization; Siglec-15 knockdown weakens TIGIT/SHP-1 activation and the inhibitory effect on M1 polarization. Co-immunoprecipitation (CA72-4/Siglec-15), Siglec-15 siRNA knockdown, ELISA for cytokines, Western blot for SHP-1 Autoimmunity Medium 41920724
2026 Genome-wide CRISPR knockout screening identifies St3gal4 (producing α2-3-linked sialic acid on N-glycans) and LRP1 as key contributors to Siglec-15 ligand expression on osteoclast precursors. LRP1 is identified as a direct Siglec-15 counter-receptor; retriever complex-mediated endosome-to-plasma membrane recycling maintains LRP1 and thus Siglec-15 ligand surface expression. St3gal4, Lrp1, and Vps35l deficiency each impair osteoclast differentiation. Genome-wide CRISPR KO screen, Siglec-15 binding assay, osteoclast differentiation assay, LRP1 expression analysis in retriever-deficient cells Cell reports High 41569849

Source papers

Stage 0 corpus · 80 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Siglec-15 as an immune suppressor and potential target for normalization cancer immunotherapy. Nature medicine 536 30833750
2021 Siglec15 shapes a non-inflamed tumor microenvironment and predicts the molecular subtype in bladder cancer. Theranostics 283 33537076
2007 Siglec-15: an immune system Siglec conserved throughout vertebrate evolution. Glycobiology 158 17483134
2012 The interaction between Siglec-15 and tumor-associated sialyl-Tn antigen enhances TGF-β secretion from monocytes/macrophages through the DAP12-Syk pathway. Glycobiology 147 23035012
2020 Siglec-15 as an Emerging Target for Next-generation Cancer Immunotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 120 32958700
2013 Siglec-15 regulates osteoclast differentiation by modulating RANKL-induced phosphatidylinositol 3-kinase/Akt and Erk pathways in association with signaling Adaptor DAP12. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 95 23677868
2012 Siglec-15 protein regulates formation of functional osteoclasts in concert with DNAX-activating protein of 12 kDa (DAP12). The Journal of biological chemistry 81 22451653
2011 Siglec-15, a member of the sialic acid-binding lectin, is a novel regulator for osteoclast differentiation. Biochemical and biophysical research communications 72 21586272
2014 Mechanism and function of monoclonal antibodies targeting siglec-15 for therapeutic inhibition of osteoclastic bone resorption. The Journal of biological chemistry 59 24446437
2019 A systems genomics approach identifies SIGLEC15 as a susceptibility factor in recurrent vulvovaginal candidiasis. Science translational medicine 51 31189718
2014 Siglec-15 is a potential therapeutic target for postmenopausal osteoporosis. Bone 48 25460183
2021 Siglec-15 Promotes Tumor Progression in Osteosarcoma via DUSP1/MAPK Pathway. Frontiers in oncology 42 34336699
2021 Siglec-15 recognition of sialoglycans on tumor cell lines can occur independently of sialyl Tn antigen expression. Glycobiology 41 32501471
2022 SIGLEC15 amplifies immunosuppressive properties of tumor-associated macrophages in pancreatic cancer. Cancer letters 39 35077803
2020 LINC00973 is involved in cancer immune suppression through positive regulation of Siglec-15 in clear-cell renal cell carcinoma. Cancer science 38 32780490
2023 Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b. Nature communications 36 37311743
2023 Osteoclast-derived apoptotic bodies inhibit naive CD8+ T cell activation via Siglec15, promoting breast cancer secondary metastasis. Cell reports. Medicine 35 37607544
2020 Integrative Analysis of Siglec-15 mRNA in Human Cancers Based on Data Mining. Journal of Cancer 34 32201516
2019 Siglec-15: An Attractive Immunotherapy Target. Cancer discovery 32 31806628
2021 Siglec-15 promotes the migration of liver cancer cells by repressing lysosomal degradation of CD44. FEBS letters 30 34328657
2020 The diverse functions of Siglec-15 in bone remodeling and antitumor responses. Pharmacological research 30 32112821
2015 Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) mediates periarticular bone loss, but not joint destruction, in murine antigen-induced arthritis. Bone 30 26027508
2021 Neuraminidase and SIGLEC15 modulate the host defense against pulmonary aspergillosis. Cell reports. Medicine 27 34095887
2022 Analysis of a novel immune checkpoint, Siglec-15, in pancreatic ductal adenocarcinoma. The journal of pathology. Clinical research 24 35083884
2021 Immunopositivity for Siglec-15 in gastric cancer and its association with clinical and pathological parameters. European journal of histochemistry : EJH 24 33666065
2023 Siglec-15 on macrophages suppress the immune microenvironment in patients with PD-L1 negative non-metastasis lung adenocarcinoma. Cancer gene therapy 21 38072971
2022 A novel immune checkpoint siglec-15 antibody inhibits LUAD by modulating mφ polarization in TME. Pharmacological research 21 35605813
2020 The significance of Siglec-15 expression in resectable non-small cell lung cancer. Neoplasma 19 32749846
2024 Targeting SIGLEC15 as an emerging immunotherapy for anaplastic thyroid cancer. International immunopharmacology 18 38652971
2021 Glycosylation of Siglec15 promotes immunoescape and tumor growth. American journal of cancer research 18 34094685
2021 Molecular structure, expression, and the emerging role of Siglec-15 in skeletal biology and cancer. Journal of cellular physiology 18 34893976
2022 Siglec15 Checkpoint Blockade for Simultaneous Immunochemotherapy and Osteolysis Inhibition in Lung Adenocarcinoma Spinal Metastasis via a Hollow Nanoplatform. Small (Weinheim an der Bergstrasse, Germany) 17 35751455
2021 High affinity monoclonal antibody targeting Siglec-15 for cancer immunotherapy. Journal of clinical and translational research 15 34988324
2023 Dynamic change in Siglec-15 expression in peritumoral macrophages confers an immunosuppressive microenvironment and poor outcome in glioma. Frontiers in immunology 14 37234161
2022 Quantitative assessment of Siglec-15 expression in lung, breast, head, and neck squamous cell carcinoma and bladder cancer. Laboratory investigation; a journal of technical methods and pathology 13 35581307
2022 Siglec-15 Regulates the Inflammatory Response and Polarization of Tumor-Associated Macrophages in Pancreatic Cancer by Inhibiting the cGAS-STING Signaling Pathway. Oxidative medicine and cellular longevity 13 36105484
2020 N-glycosylation of Siglec-15 decreases its lysosome-dependent degradation and promotes its transportation to the cell membrane. Biochemical and biophysical research communications 13 32921411
2021 Siglec-15 Is an Immune Suppressor and Potential Target for Immunotherapy in the Pre-Metastatic Lymph Node of Colorectal Cancer. Frontiers in cell and developmental biology 12 34722496
2022 Siglec15 facilitates the progression of non-small cell lung cancer and is correlated with spinal metastasis. Annals of translational medicine 11 35434017
2022 Obesity accelerates immune evasion of non-small cell lung carcinoma via TFEB-dependent upregulation of Siglec-15 and glycolytic reprogramming. Cancer letters 11 36150633
2020 Siglec-15 on Osteoclasts Is Crucial for Bone Erosion in Serum-Transfer Arthritis. Journal of immunology (Baltimore, Md. : 1950) 11 33020147
2024 Involvement of Siglec-15 in regulating RAP1/RAC signaling in cytoskeletal remodeling in osteoclasts mediated by macrophage colony-stimulating factor. Bone research 9 38849345
2022 Development of an immunohistochemical assay for Siglec-15. Laboratory investigation; a journal of technical methods and pathology 9 35459795
2022 Siglec-15 as multifunctional molecule involved in osteoclast differentiation, cancer immunity and microbial infection. Progress in biophysics and molecular biology 9 36265694
2022 Siglec-15 as a New Perspective Therapy Target in Human Giant Cell Tumor of Bone. Current oncology (Toronto, Ont.) 9 36290882
2024 The chromatin remodeling factor Arid1a cooperates with Jun/Fos to promote osteoclastogenesis by epigenetically upregulating Siglec15 expression. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 8 38477755
2023 Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy. Acta pharmaceutica Sinica. B 8 38045048
2022 Siglec-15 Silencing Inhibits Cell Proliferation and Promotes Cell Apoptosis by Inhibiting STAT1/STAT3 Signaling in Anaplastic Thyroid Carcinoma. Disease markers 8 35769818
2022 Significance of Siglec-15 expression in colorectal cancer: association with advanced disease stage and fewer tumor-infiltrating lymphocytes. The journal of pathology. Clinical research 8 36424637
2023 Transcriptional Regulation of Siglec-15 by ETS-1 and ETS-2 in Hepatocellular Carcinoma Cells. International journal of molecular sciences 7 36614238
2023 Siglec-15 Promotes Evasion of Adaptive Immunity in B-cell Acute Lymphoblastic Leukemia. Cancer research communications 7 37465593
2022 Knocking down Siglec-15 in osteosarcoma cells inhibits proliferation while promoting apoptosis and pyroptosis by targeting the Siglec-15/STAT3/Bcl-2 pathway. Advances in medical sciences 7 35398779
2023 Non-spatial and spatial heterogeneity revealed a suppressive immune feature of Siglec-15 in lung adenocarcinomas. Journal of translational medicine 6 37674198
2022 Unveiling the molecular features, relevant immune and clinical characteristics of SIGLEC15 in thyroid cancer. Frontiers in immunology 6 36159823
2024 SIGLEC15, negatively correlated with PD-L1 in HCC, could induce CD8+ T cell apoptosis to promote immune evasion. Oncoimmunology 5 38988824
2023 Enhancing the Anti-tumor Potency of a Novel Siglec-15 Antibody by Engineering its Fc-mediated Effector Functions. Journal of immunotherapy (Hagerstown, Md. : 1997) 5 37103472
2025 Siglec-15 antibody-GM-CSF chimera suppresses tumor progression via reprogramming tumor-associated macrophages. Journal for immunotherapy of cancer 4 40216442
2023 Siglec15 promotes the migration of thyroid carcinoma cells by enhancing the EGFR protein stability. Glycobiology 4 37129515
2021 A comprehensive analysis of different gene classes in pancreatic cancer: SIGLEC15 may be a promising immunotherapeutic target. Investigational new drugs 4 34515878
2024 Evasion of immunosurveillance by the upregulation of Siglec15 in bladder cancer. Journal of hematology & oncology 3 39609852
2024 Killing two birds with one stone: Siglec-15 targeting integrated bioactive glasses hydrogel for treatment of breast cancer bone metastasis. Materials today. Bio 3 39687802
2024 Siglec-15 as a potential molecule involved in osteoclast differentiation and bone metabolism. Heliyon 2 39524871
2024 Siglec15 in blood system diseases: from bench to bedside. Frontiers in immunology 2 39697338
2024 Targeting Siglec-15 mediates mitochondrial retrograde regulation of cervical cancer development. Tissue & cell 2 39756115
2023 Retracted: Siglec-15 Regulates the Inflammatory Response and Polarization of Tumor-Associated Macrophages in Pancreatic Cancer by Inhibiting the cGAS-STING Signaling Pathway. Oxidative medicine and cellular longevity 2 37388523
2025 Siglec-15 is a putative receptor for porcine epidemic diarrhea virus infection. Cellular and molecular life sciences : CMLS 1 40172660
2025 SIGLEC15 modulates the immunosuppressive microenvironment and suppresses malignant phenotypes in triple-negative breast cancer. Genes & diseases 1 41158758
2023 Core needle biopsies alter the amounts of CCR5, Siglec-15, and PD-L1 positivities in breast carcinoma. Virchows Archiv : an international journal of pathology 1 37222841
2022 [Mapping Regulatory Elements within 5' and 3' UTRs of SIGLEC15 with a Use of Reporter System]. Molekuliarnaia biologiia 1 35621101
2026 Identification of Siglec-15 as a novel target for CAR-T cell therapy in acute myeloid leukemia. International immunopharmacology 0 41558291
2026 Comprehensive identification of the genes involved in the expression of Siglec-15 ligands on osteoclast precursors. Cell reports 0 41569849
2026 Siglec‑15 dysregulation and its therapeutic implications in new‑onset type 1 diabetes. International journal of molecular medicine 0 41891952
2026 CA72-4 derived from synovial cells inhibits monosodium urate-induced macrophage M1 polarization by activating the TIGIT/SHP-1 axis through binding to Siglec-15. Autoimmunity 0 41920724
2025 Screening and preparation of nanobodies for SIGLEC-15 detection. Protein expression and purification 0 39880295
2025 The role of Siglec-15 in tumor immunity: mechanism and therapy. Molecular cancer therapeutics 0 40833001
2025 Immunochromatographic assay for rapid detection of SIGLEC15 to evaluate its therapeutic potential in cervical cancer. International journal of biological macromolecules 0 40886986
2025 Cajanin transcriptionally disrupts the Siglec15/NFATc1 signaling cascade to attenuate osteoclast fusion and bone resorption. International immunopharmacology 0 41260165
2025 Investigating the role and mechanism of methionine in different types of skeletal fluorosis based on Siglec-15 methylation. Environmental pollution (Barking, Essex : 1987) 0 41349947
2024 Siglec-15 expression in diffuse gliomas and its correlation with MRI morphologic features and apparent diffusion coefficient. Acta radiologica (Stockholm, Sweden : 1987) 0 39434541
2022 [Study on the effect and mechanisms of SIGLEC-15 on laryngeal squamous cell carcinoma]. Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery 0 35725316