Affinage

SIGLEC9

Sialic acid-binding Ig-like lectin 9 · UniProt Q9Y336

Length
463 aa
Mass
50.1 kDa
Annotated
2026-04-28
77 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Siglec-9 is an inhibitory immunomodulatory receptor expressed on myeloid cells, NK cells, T cell subsets, mast cells, and platelets that broadly dampens innate and adaptive immune activation by recognizing sialylated glycans and recruiting the tyrosine phosphatase SHP-1. Its V-set Ig domain binds α2,3- and α2,6-linked sialic acids on diverse counter-receptors — including MUC16, glycophorin A, Tamm-Horsfall protein, GPIbα, DSG2, CD59, and sialylated bacterial capsules — and also engages high-molecular-weight hyaluronan through a distinct binding site; upon engagement, ITIM-dependent SHP-1 recruitment suppresses TCR signaling (ZAP-70, NFAT), neutrophil oxidative burst and NETosis, mast cell degranulation, and macrophage pro-inflammatory cytokine production while promoting IL-10 secretion and M2/TAM polarization (PMID:15292262, PMID:15827126, PMID:18325328, PMID:37100120, PMID:28416510, PMID:26411873, PMID:33627655). A ligand-specific exception occurs with cancer-associated sialyl-Tn MUC1, where Siglec-9 instead triggers calcium flux and MEK-ERK activation without SHP-1/SHP-2 engagement, driving PD-L1 upregulation on macrophages (PMID:27595232). Siglec-9 also functions as a leukocyte counter-receptor for endothelial VAP-1/AOC3, mediating leukocyte trafficking to inflammatory sites (PMID:21821708), and acts as an immune checkpoint in multiple tumor microenvironments where its genetic deletion or antibody blockade restores anti-tumor immunity and synergizes with PD-1/PD-L1 blockade (PMID:37460871, PMID:37709296, PMID:30988027).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2000 High

    Establishing that Siglec-9 is a sialic acid-binding lectin with defined domain architecture and ITIM-bearing cytoplasmic tail resolved its molecular identity and predicted an inhibitory signaling function.

    Evidence cDNA cloning, COS cell expression, erythrocyte rosetting, mutagenesis of the essential sialic acid-binding arginine, flow cytometry expression profiling across leukocyte lineages

    PMID:10801860 PMID:10801862

    Open questions at the time
    • Downstream signaling was not yet demonstrated
    • No endogenous ligands identified beyond erythrocyte sialic acids
  2. 2001 High

    Domain-swap mutagenesis of the V-set C-C' loop between Siglec-7 and Siglec-9 revealed the structural determinant of their distinct glycan specificities, establishing the molecular basis for ligand selectivity.

    Evidence Chimeric V-set domain mutagenesis with glyco-probe binding assays in CHO cells

    PMID:11741958

    Open questions at the time
    • Full crystal or NMR structure of the V-set domain not yet determined
    • In vivo relevance of specificity differences unknown
  3. 2004 High

    Reconstitution in Jurkat T cells demonstrated that Siglec-9 ITIM recruits SHP-1 upon TCR stimulation, suppresses ZAP-70 phosphorylation and NFAT transcriptional activity, directly proving its inhibitory signaling function.

    Evidence Stable transfection in Jurkat cells, SHP-1 co-immunoprecipitation, NFAT-luciferase reporter, R120 mutagenesis

    PMID:15292262

    Open questions at the time
    • Whether both cytoplasmic tyrosines contribute equally was unclear
    • Endogenous ligands triggering this pathway in vivo not identified
  4. 2005 High

    Demonstrating that Siglec-9 ligation induces both caspase-dependent apoptosis and a distinct caspase-independent death in cytokine-primed neutrophils revealed cell-context-dependent functional outcomes.

    Evidence Anti-Siglec-9 ligation on primary neutrophils, caspase inhibitors, ROS scavengers, ROS-deficient patient neutrophils

    PMID:15827126

    Open questions at the time
    • Identity of the endogenous neutrophil Siglec-9 ligand triggering these pathways was unknown
    • Molecular mechanism of the non-apoptotic death pathway unresolved
  5. 2008 High

    ITIM tyrosine mutagenesis in macrophages separated IL-10 enhancement from TNF-α suppression, showing that the two ITIM motifs differentially regulate anti- versus pro-inflammatory cytokines.

    Evidence Wild-type and ITIM-mutant Siglec-9 in RAW264/THP-1 macrophages, TLR stimulation, cytokine ELISA

    PMID:18325328

    Open questions at the time
    • Which phosphatase or adaptor is recruited by each individual ITIM was not resolved
    • In vivo macrophage polarization consequences not tested
  6. 2009 High

    Group B Streptococcus sialylated capsule was shown to engage neutrophil Siglec-9 to suppress oxidative burst and NET formation, establishing molecular mimicry as a pathogen immune evasion strategy via Siglec-9.

    Evidence Isogenic GBS sialic acid-deficient mutants, neutrophil functional assays, Siglec-9 blocking

    PMID:19196661

    Open questions at the time
    • Whether this extends to other sialylated pathogens beyond GBS was not known
    • Relative contribution of Siglec-9 vs. other siglecs on neutrophils not quantified
  7. 2010 High

    MUC16 on ovarian cancer cells was identified as a sialic acid-dependent Siglec-9 ligand on immune cells, providing the first tumor-associated glycoprotein counter-receptor for Siglec-9.

    Evidence Siglec-9 transfection of Jurkat cells, neuraminidase treatment, cell adhesion assays

    PMID:20497550

    Open questions at the time
    • Whether MUC16–Siglec-9 interaction drives functional immune suppression in ovarian cancer was not yet shown
    • Specific glycan structures on MUC16 mediating binding not characterized
  8. 2011 High

    Identification of Siglec-9 as a leukocyte counter-receptor for endothelial VAP-1/AOC3 expanded its role beyond immune inhibition to leukocyte trafficking, with binding mapped to the VAP-1 enzymatic groove.

    Evidence Phage display, in vitro/ex vivo adhesion assays, VAP-1 mutant proteins, PET imaging with labeled Siglec-9 peptide

    PMID:21821708

    Open questions at the time
    • Whether Siglec-9–VAP-1 interaction is sialic acid-dependent or peptide-mediated was not fully resolved
    • In vivo genetic evidence for this trafficking axis not provided
  9. 2013 Medium

    Discovery that Siglec-9 binding to sialylated MUC1 on cancer cells activates β-catenin nuclear translocation and that prohibitins serve as sialic acid-independent Siglec-9 counter-receptors on T cells broadened the receptor's signaling repertoire beyond simple inhibition.

    Evidence Co-culture systems with β-catenin co-IP and nuclear fractionation (MUC1); co-IP and ERK/c-Raf signaling with R120A mutagenesis (prohibitins)

    PMID:23567969 PMID:24045940

    Open questions at the time
    • β-catenin activation by Siglec-9 not confirmed in primary tumor models
    • Prohibitin binding being sialic acid-independent is unusual and the structural basis is unresolved
    • Single-lab findings for both observations
  10. 2014 Medium

    Siglec-9 was shown to translocate to lipid raft microdomains upon TLR2 stimulation in a lectin-dependent manner, linking its spatial membrane organization to IL-10 regulatory output.

    Evidence Membrane fractionation, lectin-defective mutant, cholesterol disruption, TLR2 stimulation in macrophages

    PMID:24449467

    Open questions at the time
    • Direct visualization of Siglec-9 in rafts (e.g. super-resolution microscopy) not performed
    • Whether raft localization is required for SHP-1 recruitment not tested
  11. 2015 High

    Identification of HMW-hyaluronan as a non-sialic acid ligand binding a distinct site on Siglec-9's V-set domain, exploited by Group A Streptococcus capsule, revealed a second ligand-recognition mode for immune evasion.

    Evidence HMW-HA binding assays, neutrophil functional assays, GAS capsule competition, Siglec-9 blocking antibodies

    PMID:26411873

    Open questions at the time
    • Structural mapping of the HMW-HA binding site not determined at atomic resolution
    • Physiological role of HMW-HA–Siglec-9 in tissue homeostasis not established
  12. 2016 High

    MUC1-ST engagement of Siglec-9 on macrophages was shown to paradoxically activate MEK-ERK and calcium signaling without SHP-1/SHP-2 recruitment, driving TAM polarization and PD-L1 upregulation — fundamentally revising the view that Siglec-9 is exclusively inhibitory.

    Evidence MUC1-ST binding assays, calcium flux, phosphatase activity assays, MEK-ERK immunoblotting, PD-L1 flow cytometry

    PMID:27595232

    Open questions at the time
    • How ligand identity switches Siglec-9 from SHP-1-dependent inhibition to MEK-ERK activation is mechanistically unresolved
    • Whether this activating mode occurs with other cancer glycoforms is unknown
  13. 2017 High

    Glycophorin A and Tamm-Horsfall protein were identified as physiological Siglec-9 ligands that suppress neutrophil activation in blood and urinary tract, respectively, establishing tissue-specific immune dampening through distinct sialoglycoprotein ligands.

    Evidence Sialic acid oxidation on erythrocytes, THP-null mouse model, neuraminidase controls, multiple neutrophil functional assays

    PMID:28416510 PMID:28829050

    Open questions at the time
    • In vivo human genetic validation of GYPA–Siglec-9 axis missing
    • Whether other urinary sialoglycoproteins contribute beyond THP not addressed
  14. 2019 High

    Siglec-9+ CD8+ T cells in melanoma were shown to be functionally inhibited through SHP-1 (not SHP-2) phosphorylation, formally establishing Siglec-9 as a T cell immune checkpoint in the tumor microenvironment.

    Evidence Flow cytometry of intratumoral T cells, agonist antibodies, SHP-1/SHP-2 phosphorylation, cytotoxicity assays

    PMID:30988027

    Open questions at the time
    • Clinical impact of Siglec-9 blockade on T cells not tested in patients
    • Relative importance vs. PD-1/CTLA-4 checkpoints not compared
  15. 2021 High

    ST3GAL1/ST3GAL4 sialyltransferases were identified as the enzymes generating Siglec-9 ligands on PDAC cells, mechanistically connecting glycan biosynthesis to myeloid immunosuppression, while synthetic Siglec-9 agonist glycopolymers were shown to suppress NETosis, demonstrating pharmacological tractability.

    Evidence siRNA knockdown of ST3GAL1/4 with binding and macrophage differentiation assays; synthetic glycopolymer Siglec-9 agonism with NETosis assays

    PMID:33627655 PMID:34056095

    Open questions at the time
    • Whether blocking sialyltransferases therapeutically is feasible in vivo not shown
    • Off-target effects of glycopolymer agonists on other siglecs not fully excluded
  16. 2023 High

    Genetic deletion of Siglec-9 (Siglece in mice) on macrophages in glioblastoma restored antigen presentation and T cell activation, synergizing with anti-PD-1, while CRISPR knockout on human mast cells increased degranulation — demonstrating checkpoint function across multiple immune cell types.

    Evidence Siglece knockout mice with tumor models, scRNA-seq, spatial transcriptomics, CRISPR/Cas9 SIGLEC9 KO in human mast cells, co-engagement assays

    PMID:37100120 PMID:37460871

    Open questions at the time
    • Species differences between murine Siglec-E and human Siglec-9 may limit translational inference
    • Mast cell Siglec-9 signaling pathway details beyond ITIM not characterized
  17. 2024 High

    Atomic-level understanding of ligand recognition was achieved by NMR, and new ligand axes were identified: ST3GAL4-dependent sialylation drives Siglec-9 engagement on AML cells controlling phagocytosis; Omicron SARS-CoV-2 RBD FAPFFAF motif directly binds Siglec-9 to suppress macrophage function; and CD59 is a Siglec-9 ligand in prostate cancer.

    Evidence NMR/MD simulations of V-set domain; CRISPR screen and glycoproteomics in AML; spike mutagenesis (F375S) with macrophage assays and vaccine immunogenicity; CRISPRi screen in prostate cancer xenografts

    PMID:38321945 PMID:38454157 PMID:39436703 PMID:39551873

    Open questions at the time
    • Full co-crystal structure of Siglec-9 with a glycoprotein ligand not yet solved
    • Whether SARS-CoV-2 binding is sialic acid-dependent or protein-mediated is not fully delineated
    • CD59 as Siglec-9 ligand requires independent replication
  18. 2025 High

    DSG2 was identified as a dominant melanoma ligand for Siglec-9 via proximity labeling, and GPIbα was shown to cis-engage Siglec-9 on platelets to suppress coagulation, extending Siglec-9's inhibitory function to hemostasis.

    Evidence Proximity labeling plus CRISPR KO screening in melanoma; conditional Siglec-E knockout in mouse platelets with human platelet in vitro validation

    PMID:39813162 PMID:40204021

    Open questions at the time
    • DSG2 finding from single lab awaiting independent replication
    • Whether platelet Siglec-9 contributes to bleeding phenotypes in humans is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how ligand identity switches Siglec-9 between SHP-1-dependent inhibition and MEK-ERK activation, the structural basis for non-sialic acid ligand recognition (HMW-HA, prohibitins, viral RBD), and whether therapeutic Siglec-9 blockade or agonism can be translated to clinical benefit in cancer and inflammatory disease.
  • No co-crystal structure with a glycoprotein ligand
  • Mechanism of ligand-dependent signaling mode switching unresolved
  • Clinical-grade Siglec-9 blocking or agonist agents not yet in trials

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 5 GO:0098772 molecular function regulator activity 5
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 6 R-HSA-109582 Hemostasis 1
Partners
AOC3CD59DSG2GP1BAGYPAMUC1MUC16SHP-1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Siglec-9 is a type I transmembrane protein with three extracellular Ig-like domains (N-terminal V-set and two C2-set domains), a transmembrane region, and a cytoplasmic tail containing two tyrosine-based signaling motifs (one ITIM). Expression of full-length cDNA in COS cells induces sialic-acid-dependent erythrocyte binding. Recombinant soluble extracellular domain binds α2-3 and α2-6-linked sialic acids; mutation of a critical arginine in domain 1 abrogates binding. cDNA cloning, COS cell expression, erythrocyte binding assay, recombinant protein binding assay, site-directed mutagenesis The Journal of biological chemistry High 10801860
2000 Siglec-9 is expressed at high or intermediate levels on monocytes, neutrophils, and a minor CD16+/CD56- population; weaker expression on ~50% of B cells and NK cells and minor CD8+ and CD4+ T cell subsets. Binding assays confirmed recognition of sialic acid in α2,3- or α2,6-glycosidic linkage to galactose. Flow cytometry with specific mAb, binding assays The Journal of biological chemistry High 10801862
2001 The C-C' loop region (residues Asn70–Lys75) in the V-set sugar-binding domain determines the differential glycan binding specificities of Siglec-7 vs. Siglec-9. Siglec-9 binds LSTc and GD1a oligosaccharides but not GD3 and LSTb, whereas Siglec-7 shows the opposite preference. Substituting this region between the two siglecs swaps their binding specificities. Chimeric V-set domain mutagenesis, polyvalent glyco-probe binding assays on CHO cells, molecular modeling The Journal of biological chemistry High 11741958
2004 Siglec-9 negatively regulates T cell receptor (TCR) signaling: upon TCR engagement or pervanadate stimulation, Siglec-9 undergoes tyrosine phosphorylation and recruits SHP-1, reduces phosphorylation of ZAP-70 at Tyr319, and decreases NFAT transcriptional activity. Mutation of the conserved Arg120 in the ligand-binding site reduces inhibitory function, demonstrating that sialic acid ligand binding is required for optimal inhibition. Stable/transient transfection of Jurkat T cells, TCR stimulation assays, SHP-1 co-immunoprecipitation, NFAT/luciferase reporter, site-directed mutagenesis The Journal of biological chemistry High 15292262
2005 Siglec-9 ligation on neutrophils initiates two death pathways: (1) apoptotic (ROS- and caspase-dependent) under normal conditions, and (2) nonapoptotic/caspase-independent death (characterized by cytoplasmic vacuolization and ROS-dependence) when neutrophils are primed with proinflammatory cytokines (GM-CSF, IFN-α, IFN-γ). ROS scavengers and ROS-deficient neutrophils block both pathways. Siglec-9 ligation on primary neutrophils, caspase inhibitor assays, ROS scavenger experiments, ROS-deficient patient neutrophils, morphological analysis Blood High 15827126
2008 Siglec-9 enhances IL-10 production and suppresses TNF-α in macrophages via its cytoplasmic tyrosine-based inhibitory motifs (ITIM). Mutation of both cytoplasmic tyrosines to phenylalanine abolishes the IL-10 enhancement and TNF-α suppression. The membrane-proximal ITIM mutant retains partial TNF-α suppression but loses IL-10 upregulation, indicating distinct regulation of the two cytokines through different ITIM residues. Stable transfection of RAW264 and THP-1 macrophage lines with wild-type and ITIM-mutant Siglec-9; LPS/CpG/PGN stimulation; ELISA for TNF-α and IL-10 Biochemical and biophysical research communications High 18325328
2009 Group B Streptococcus (GBS) sialylated capsular polysaccharide (Siaα2-3Galβ1-4GlcNAc) engages neutrophil Siglec-9 via molecular mimicry of host sialoglycans. This interaction dampens neutrophil oxidative burst, reduces NETs formation, and increases bacterial survival. Effects are Sia- and Siglec-9-dependent. Neutrophil functional assays (oxidative burst, NET formation, bacterial killing) with GBS wild-type and sialic acid-deficient mutants; immobilized synthetic sialoglycan binding; Siglec-9 blocking Blood High 19196661
2009 Siglec-9 physically interacts with SHP-1 in neutrophils; GM-CSF treatment promotes Siglec-9 phosphorylation in adult PMN but decreases it in neonatal PMN. Neonatal PMN display diminished Siglec-9 expression and constitutive phosphorylation at baseline, associated with altered survival signaling. Co-immunoprecipitation of Siglec-9 and SHP-1 from neutrophil lysates; immunoblotting; flow cytometry; GM-CSF stimulation experiments Pediatric research Medium 19542910
2010 MUC16 (CA125) expressed on ovarian cancer cells is identified as the ligand for Siglec-9 on NK cells, B cells, and monocytes. Siglec-9-transfected Jurkat cells and monocytes bind to ovarian tumor cells via Siglec-9–csMUC16 interaction; binding is abolished by neuraminidase treatment, confirming sialic acid dependence. Siglec-9 transfection of Jurkat cells, neuraminidase treatment, cell adhesion assays, flow cytometry of patient peripheral blood and peritoneal fluid immune cells Molecular cancer High 20497550
2011 Siglec-9 is a leukocyte counter-receptor for vascular adhesion protein-1 (VAP-1/AOC3) on endothelium. The interaction was identified by phage display, confirmed by in vitro and ex vivo adhesion assays, and the binding site was mapped to the enzymatic groove of VAP-1 by molecular modeling and mutant protein assays. Binding is only partially dependent on VAP-1 enzymatic activity. A 68Ga-labeled Siglec-9 peptide specifically detects VAP-1 at inflammatory sites in PET imaging. Phage display, in vitro and ex vivo adhesion assays, binding assays with mutated VAP-1 proteins, molecular modeling, PET imaging Blood High 21821708
2013 Siglec-9 binding to sialylated MUC1 on cancer cells recruits β-catenin to the MUC1 C-terminal domain in a dose- and time-dependent manner, and the recruited β-catenin translocates to the nucleus to promote cell growth. Neuraminidase treatment abolishes the effect, confirming sialic acid dependence. Co-culture of Siglec-9-expressing HEK293 cells with MUC1-expressing 3T3 and HCT116 cells; β-catenin co-immunoprecipitation and nuclear fractionation; neuraminidase treatment; recombinant soluble Siglec-9 stimulation The Journal of biological chemistry High 24045940
2013 Siglec-9 binding to sialoglycans on astrocytoma cells causes rapid calpain-mediated degradation of focal adhesion kinase (FAK), Akt, paxillin, and p130Cas, leading to cell detachment, increased motility, and invasiveness. Calpain inhibitors block these effects. Co-culture of Siglec-9-expressing cells with AS astrocytoma cells; immunoblotting for FAK, Akt, paxillin, p130Cas; calpain inhibitor experiments; motility and invasion assays The Journal of biological chemistry Medium 24145038
2013 Prohibitin-1 and -2 on the surface of T cell lines and activated T lymphocytes act as counter-receptors for Siglec-9 on macrophages/DCs, binding in a sialic acid-independent manner. Mutation of Arg120 to Ala in Siglec-9 abolishes binding, suggesting ionic peptide-peptide interaction. Siglec-9 engagement of prohibitins inhibits ERK1/2 and c-Raf phosphorylation and reduces IL-2 production in Jurkat cells. Co-immunoprecipitation, bead-based TCR co-stimulation assay with Siglec-9, site-directed mutagenesis (Arg120Ala), immunoblotting for ERK1/2 and c-Raf, IL-2 ELISA Biochemical and biophysical research communications Medium 23567969
2014 Siglec-9 localizes partially to lipid raft (detergent-insoluble microdomain) fractions, and this localization is lectin (sialic acid-binding) dependent. Following TLR2 stimulation, the amount of Siglec-9 in lipid rafts rapidly increases within 3–10 minutes, coinciding with TLR2 recruitment. Lectin-defective Siglec-9 does not enter lipid rafts, and disruption of lipid rafts partially reduces IL-10 production. Membrane fractionation, detergent-insoluble microdomain isolation, immunoblotting, lectin-defective Siglec-9 mutant, cholesterol oxidase disruption, TLR2 stimulation Cytotechnology Medium 24449467
2015 Siglec-9 specifically binds high molecular weight hyaluronan (HMW-HA) through a region of the V-set Ig-like domain distinct from the canonical sialic acid-binding site, dampening neutrophil NET formation, oxidative burst, and apoptosis. Group A Streptococcus exploits its HMW-HA capsule to engage this same Siglec-9 binding site, blocking neutrophil killing. HMW-HA binding assays, neutrophil functional assays (NET formation, oxidative burst, apoptosis), GAS HMW-HA capsule competition experiments, Siglec-9 blocking antibodies Journal of molecular medicine High 26411873
2015 Siglec-9 modulates IL-4 responses in macrophages via its cytoplasmic ITIM motifs: Siglec-9 expression enhances arginase-1 (Arg1) induction by IL-4 through MEK/ERK pathway activation. Mutation of cytoplasmic tyrosines in ITIM markedly reduces Arg1 expression. ERK phosphorylation is enhanced basally and MEK inhibitors block the Siglec-9-augmented Arg1 induction, whereas PI-3K inhibitors do not. Stable transfection of RAW264 with wild-type and ITIM-mutant Siglec-9; IL-4 stimulation; immunoblotting for Akt and ERK phosphorylation; MEK and PI-3K inhibitor treatment; arginase-1 expression assay Bioscience, biotechnology, and biochemistry Medium 26540411
2016 Cancer-specific MUC1 decorated with short sialylated O-linked glycans (MUC1-ST) engages Siglec-9 on myeloid cells and induces macrophage polarization to a TAM-like phenotype with upregulated PD-L1. Unexpectedly, MUC1-ST/Siglec-9 engagement does not activate SHP-1 or SHP-2 but induces calcium flux leading to MEK-ERK kinase activation. MUC1-ST–Siglec-9 binding assays, macrophage co-culture, phosphatase activity assays (SHP-1, SHP-2), calcium flux assay, MEK-ERK phosphorylation immunoblotting, PD-L1 flow cytometry Nature immunology High 27595232
2017 Erythrocyte glycophorin A (GYPA), the most abundant sialoglycoprotein on erythrocytes, engages neutrophil Siglec-9 to suppress neutrophil activation (oxidative burst, NET formation, l-selectin shedding, chemotaxis, bacterial killing, and apoptosis). Selective oxidation of sialic acid side chains on erythrocytes reduces Siglec-9 binding and restores neutrophil activation. Whole blood vs. purified neutrophil comparison, sodium metaperiodate sialic acid oxidation, ELISA and immunofluorescence for GYPA-Siglec-9 engagement, multiple neutrophil functional assays Blood High 28416510
2017 Tamm-Horsfall glycoprotein (THP) engages Siglec-9 (and mouse Siglec-E) on neutrophils in a sialic acid (N-glycan)-dependent manner, reducing ROS generation, chemotaxis, and uropathogenic E. coli killing. THP-null mice exhibit significantly more neutrophils in urine, demonstrating a physiological role for THP-Siglec-9 interaction in limiting urinary tract inflammation. THP-neutrophil binding assays, neuraminidase treatment, neutrophil functional assays, THP-null mouse model, Siglec-E involvement confirmed Immunology and cell biology High 28829050
2017 Soluble Siglec-9 suppresses M1 macrophage activation by inhibiting NF-κB p65 phosphorylation, reduces M1 marker expression (TNF-α, IL-6, iNOS) in RAW264.7 cells, and decreases clinical/histological arthritis severity in collagen-induced arthritis mice, increasing Foxp3+ Treg cells and decreasing serum TNF-α. RAW264.7 macrophage stimulation assays, NF-κB pathway immunoblotting, collagen-induced arthritis mouse model, in vivo biofluorescence imaging, histology Arthritis research & therapy Medium 27267914
2019 Siglec-9+ CD8+ T cells in melanoma tumors are functionally inhibited by Siglec-9 engagement: ligation with Siglec-9 ligands or specific antibodies suppresses TCR signaling, cytotoxicity, and cytokine production, associated with phosphorylation of SHP-1 but not SHP-2. Flow cytometry of intratumoral vs. peripheral CD8+ T cells, Siglec-9 ligand functional assays, agonist antibody stimulation, SHP-1/SHP-2 phosphorylation immunoblotting, cytotoxicity and cytokine assays Cancer immunology research High 30988027
2021 Pancreatic ductal adenocarcinoma (PDAC) sialic acids synthesized by ST3GAL1 and ST3GAL4 sialyltransferases are recognized by Siglec-9 on myeloid cells, driving monocyte-to-TAM differentiation. Siglec-9 triggering in macrophages reduces inflammatory programs and increases PD-L1 and IL-10 expression. siRNA knockdown of ST3GAL1/ST3GAL4, Siglec-9 binding assays with PDAC cells, monocyte differentiation assays, PD-L1 and IL-10 expression, single-cell and bulk transcriptomics Nature communications High 33627655
2021 Synthetic glycopolymers that act as Siglec-9 agonists suppress NETosis in neutrophils induced by viral TLR agonists and plasma from COVID-19 patients, demonstrating that pharmacological Siglec-9 activation is sufficient to inhibit neutrophil hyperactivation. Synthetic glycopolymer-mediated Siglec-9 agonism, NETosis assays with TLR agonists and COVID-19 patient plasma ACS central science Medium 34056095
2023 Siglec-9 acts as an immune checkpoint on macrophages in glioblastoma: Siglec-9 (murine homolog Siglece) deletion activates CD4+ and CD8+ T cells through enhanced antigen presentation, secreted chemokines, and co-stimulatory factor interactions, and synergizes with anti-PD-1/PD-L1 therapy to suppress tumor growth. Single-cell RNA sequencing, spatial transcriptomics, Siglece knockout mouse models, tumor growth assays, T cell activation assays Nature cancer High 37460871
2023 Siglec-9 is an inhibitory receptor on human mast cells: CRISPR/Cas9 disruption of SIGLEC9 results in increased baseline activation markers and increased responsiveness to IgE-dependent and -independent stimulation. Co-engagement of Siglec-9 with FcεRI reduces degranulation, arachidonic acid production, and chemokine release. Glycophorin A and HMW-HA act as Siglec-9 ligands on mast cells. CRISPR/Cas9 SIGLEC9 knockout in human mast cells, FcεRI co-engagement assays, degranulation assays, arachidonic acid and cytokine measurement, flow cytometry The Journal of allergy and clinical immunology High 37100120
2023 Blockade of Siglec-9 on TAMs in ovarian cancer suppresses SHP-1 phosphorylation, repolarizes TAMs to an antitumorigenic phenotype, and restores cytotoxic CD8+ T cell activity in vitro and ex vivo. Flow cytometry, anti-Siglec-9 blocking antibody treatment, SHP-1 phosphorylation assay, macrophage repolarization assays, CD8+ T cell cytotoxicity assays Journal for immunotherapy of cancer Medium 37709296
2024 NMR spectroscopy and molecular dynamics simulations revealed that Neu5Ac is accommodated at the canonical sialic acid-binding site between the F and G β-strands of Siglec-9's V-set domain. Modified sialoglycans with a heteroaromatic scaffold at C9 of Neu5Ac create new interactions with hydrophobic residues at the G-G' loop and N-terminal region; additions at C5 of Neu5Ac stabilize the flexible B'-C loop, explaining enhanced affinity. Solution NMR spectroscopy (triple resonance 3D NMR backbone assignment), molecular dynamics simulation, binding assays with natural and synthetic sialoglycans ACS chemical biology High 38321945
2024 ST3GAL4 sialyltransferase is the primary driver of Siglec-9 ligand (α2,3-sialylated N-linked glycan) synthesis in AML cells. CRISPR-Cas9 knockout of ST3GAL4 dramatically reduces Siglec-9 ligand expression and enhances phagocytosis of AML cells by Siglec-9-expressing macrophages. CRISPR genomic screening, ST3GAL4 CRISPR-Cas9 KO, mass spectrometry glycan analysis, Siglec-9 binding assays, macrophage phagocytosis assays Leukemia High 39551873
2024 Omicron SARS-CoV-2 RBD binds Siglec-9 on macrophages via the FAPFFAF sequence (positions 371-377); a phenylalanine-to-serine mutation at F375 (F375S) abrogates Siglec-9 binding, restores macrophage phagocytosis and antigen presentation, and enhances immunogenicity of Omicron vaccines. Reverse mutagenesis of spike protein, Siglec-9 binding assays, macrophage phagocytosis assays, antigen presentation assays, mouse/rabbit/macaque vaccine immunogenicity Nature immunology High 38454157
2024 Sialylated CD59 was identified as a candidate Siglec-9 ligand in prostate cancer using a CRISPRi screen combined with mass spectrometry. Blocking Siglec-7/9–sialic acid interactions inhibited prostate cancer xenograft growth in humanized mice. CRISPRi screen, mass spectrometry, Siglec-9 ligand binding assays, xenograft mouse model with humanized immune system The Journal of clinical investigation Medium 39436703
2025 DSG2 (Desmoglein 2) is identified as a dominant counter-receptor of Siglec-9 in melanoma cells via proximity labeling combined with CRISPR KO screening. The interaction is primarily dependent on sialic acid-bearing N-glycans on DSG2, and blocking DSG2–Siglec-9 significantly enhances macrophage phagocytosis of melanoma cells. Proximity labeling, CRISPR KO screening, Siglec-9 binding assays, N-glycan dependency assays, macrophage phagocytosis assays Advanced science Medium 39813162
2025 Siglec-9 suppresses platelet activation through cis-binding to the mucin-like region of GPIbα carrying O-linked α2,3-sialylated glycans on the platelet surface. Conditional knockout of Siglec-E in platelets (platelet factor 4-cre:Siglec-Eflox/flox) increases platelet coagulation activities in vitro and in vivo. The cis-binding GPIbα–Siglec-9 interaction acts as a 'parking brake' on platelet activation. Conditional Siglec-E knockout mouse model, human platelet in vitro culture, recombinant GPIbα glycoprotein binding assays, neuraminidase treatment, platelet coagulation assays Journal of thrombosis and haemostasis High 40204021
2006 Siglec-9 mediates rapid endocytosis of anti-Siglec-9 antibody in AML cells and rat basophilic leukemia cells transfected with Siglec-9, identifying it as an endocytic receptor absent from normal bone marrow myeloid progenitors. Anti-Siglec-9 mAb endocytosis assays in primary AML cells and transfected RBL cells, flow cytometry Leukemia research Medium 16828866

Source papers

Stage 0 corpus · 77 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Molecular mimicry of host sialylated glycans allows a bacterial pathogen to engage neutrophil Siglec-9 and dampen the innate immune response. Blood 315 19196661
2016 The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9. Nature immunology 306 27595232
2021 Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9. Nature communications 243 33627655
2000 Siglec-9, a novel sialic acid binding member of the immunoglobulin superfamily expressed broadly on human blood leukocytes. The Journal of biological chemistry 189 10801862
2005 Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment. Blood 181 15827126
2023 Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response. Nature cancer 173 37460871
2010 Identification of Siglec-9 as the receptor for MUC16 on human NK cells, B cells, and monocytes. Molecular cancer 170 20497550
2001 A small region of the natural killer cell receptor, Siglec-7, is responsible for its preferred binding to alpha 2,8-disialyl and branched alpha 2,6-sialyl residues. A comparison with Siglec-9. The Journal of biological chemistry 166 11741958
2004 Negative regulation of T cell receptor signaling by Siglec-7 (p70/AIRM) and Siglec-9. The Journal of biological chemistry 160 15292262
2000 Cloning, characterization, and phylogenetic analysis of siglec-9, a new member of the CD33-related group of siglecs. Evidence for co-evolution with sialic acid synthesis pathways. The Journal of biological chemistry 132 10801860
2019 Siglec-9 Regulates an Effector Memory CD8+ T-cell Subset That Congregates in the Melanoma Tumor Microenvironment. Cancer immunology research 126 30988027
2011 Siglec-9 is a novel leukocyte ligand for vascular adhesion protein-1 and can be used in PET imaging of inflammation and cancer. Blood 104 21821708
2008 Siglec-9 enhances IL-10 production in macrophages via tyrosine-based motifs. Biochemical and biophysical research communications 86 18325328
2017 Erythrocyte sialoglycoproteins engage Siglec-9 on neutrophils to suppress activation. Blood 85 28416510
2017 Siglec-8 and Siglec-9 binding specificities and endogenous airway ligand distributions and properties. Glycobiology 81 28369504
2015 Host and pathogen hyaluronan signal through human siglec-9 to suppress neutrophil activation. Journal of molecular medicine (Berlin, Germany) 73 26411873
2013 Binding of the sialic acid-binding lectin, Siglec-9, to the membrane mucin, MUC1, induces recruitment of β-catenin and subsequent cell growth. The Journal of biological chemistry 66 24045940
2010 Immunomodulation of monocyte-derived dendritic cells through ligation of tumor-produced mucins to Siglec-9. Biochemical and biophysical research communications 66 20971061
2021 Synthetic Siglec-9 Agonists Inhibit Neutrophil Activation Associated with COVID-19. ACS central science 52 34056095
2015 Expression of ligands for Siglec-8 and Siglec-9 in human airways and airway cells. The Journal of allergy and clinical immunology 52 25747723
2006 Analysis of the CD33-related siglec family reveals that Siglec-9 is an endocytic receptor expressed on subsets of acute myeloid leukemia cells and absent from normal hematopoietic progenitors. Leukemia research 51 16828866
2020 The Roles of Siglec7 and Siglec9 on Natural Killer Cells in Virus Infection and Tumour Progression. Journal of immunology research 45 32322597
2021 Development of Siglec-9 Blocking Antibody to Enhance Anti-Tumor Immunity. Frontiers in oncology 37 34869028
2016 Soluble Siglec-9 suppresses arthritis in a collagen-induced arthritis mouse model and inhibits M1 activation of RAW264.7 macrophages. Arthritis research & therapy 34 27267914
2024 Sialylated glycoproteins suppress immune cell killing by binding to Siglec-7 and Siglec-9 in prostate cancer. The Journal of clinical investigation 33 39436703
2000 Identification and molecular characterization of a novel member of the siglec family (SIGLEC9). Genomics 33 10903842
2018 Decreased Siglec-9 Expression on Natural Killer Cell Subset Associated With Persistent HBV Replication. Frontiers in immunology 32 29899741
2017 Secreted Ectodomain of SIGLEC-9 and MCP-1 Synergistically Improve Acute Liver Failure in Rats by Altering Macrophage Polarity. Scientific reports 31 28272428
2023 LINC01004-SPI1 axis-activated SIGLEC9 in tumor-associated macrophages induces radioresistance and the formation of immunosuppressive tumor microenvironment in esophageal squamous cell carcinoma. Cancer immunology, immunotherapy : CII 29 36688997
2017 Tamm-Horsfall glycoprotein engages human Siglec-9 to modulate neutrophil activation in the urinary tract. Immunology and cell biology 28 28829050
2017 Increased expression of Siglec-9 in chronic obstructive pulmonary disease. Scientific reports 27 28860481
2016 Influence of SIGLEC9 polymorphisms on COPD phenotypes including exacerbation frequency. Respirology (Carlton, Vic.) 27 27878892
2016 Regulation of airway inflammation by Siglec-8 and Siglec-9 sialoglycan ligand expression. Current opinion in allergy and clinical immunology 26 26694037
2018 Targeting Neutrophils in Severe Asthma via Siglec-9. International archives of allergy and immunology 23 29306942
2014 A soluble form of Siglec-9 provides an antitumor benefit against mammary tumor cells expressing MUC1 in transgenic mice. Biochemical and biophysical research communications 22 24924635
2021 Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells. PLoS pathogens 20 34762717
2009 Siglec-9 and SHP-1 are differentially expressed in neonatal and adult neutrophils. Pediatric research 20 19542910
2023 Siglec-9+ tumor-associated macrophages delineate an immunosuppressive subset with therapeutic vulnerability in patients with high-grade serous ovarian cancer. Journal for immunotherapy of cancer 19 37709296
2023 Siglec-9 is an inhibitory receptor on human mast cells in vitro. The Journal of allergy and clinical immunology 18 37100120
2022 Siglec-9, a Putative Immune Checkpoint Marker for Cancer Progression Across Multiple Cancer Types. Frontiers in molecular biosciences 18 35372497
2016 Feasibility of (68)Ga-labeled Siglec-9 peptide for the imaging of acute lung inflammation: a pilot study in a porcine model of acute respiratory distress syndrome. American journal of nuclear medicine and molecular imaging 18 27069763
2019 Decreased erythrocyte binding of Siglec-9 increases neutrophil activation in sickle cell disease. Blood cells, molecules & diseases 16 31901888
2016 A soluble form of Siglec-9 provides a resistance against Group B Streptococcus (GBS) infection in transgenic mice. Microbial pathogenesis 16 27544323
2017 Siglec-9 is upregulated in rheumatoid arthritis and suppresses collagen-induced arthritis through reciprocal regulation of Th17-/Treg-cell differentiation. Scandinavian journal of immunology 15 28273363
2024 The glycosyltransferase ST3GAL4 drives immune evasion in acute myeloid leukemia by synthesizing ligands for the glyco-immune checkpoint receptor Siglec-9. Leukemia 14 39551873
2023 Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2. mBio 14 36728420
2016 Constitutively expressed Siglec-9 inhibits LPS-induced CCR7, but enhances IL-4-induced CD200R expression in human macrophages. Bioscience, biotechnology, and biochemistry 14 26923638
2020 Soluble Siglec-9 alleviates intestinal inflammation through inhibition of the NF-κB pathway. International immunopharmacology 13 32570035
2015 Siglec-9 modulated IL-4 responses in the macrophage cell line RAW264. Bioscience, biotechnology, and biochemistry 13 26540411
2024 The receptor binding domain of SARS-CoV-2 Omicron subvariants targets Siglec-9 to decrease its immunogenicity by preventing macrophage phagocytosis. Nature immunology 12 38454157
2013 Binding of a sialic acid-recognizing lectin Siglec-9 modulates adhesion dynamics of cancer cells via calpain-mediated protein degradation. The Journal of biological chemistry 12 24145038
2013 Prohibitins function as endogenous ligands for Siglec-9 and negatively regulate TCR signaling upon ligation. Biochemical and biophysical research communications 10 23567969
2024 Targeting Tumor-Associated Sialic Acids Using Chimeric Switch Receptors Based on Siglec-9 Enhances the Antitumor Efficacy of Engineered T Cells. Cancer immunology research 9 39037052
2023 Sialic Acids on Tumor Cells Modulate IgA Therapy by Neutrophils via Inhibitory Receptors Siglec-7 and Siglec-9. Cancers 9 37444515
2022 Development of Effective Siglec-9 Antibodies Against Cancer. Current oncology reports 9 36445569
2024 Unraveling Molecular Recognition of Glycan Ligands by Siglec-9 via NMR Spectroscopy and Molecular Dynamics Modeling. ACS chemical biology 8 38321945
2024 Expression of Siglec-9 in peripheral blood neutrophils was increased and associated with disease severity in patients with AECOPD. Cytokine 8 38412768
2014 Dasatinib enhances migration of monocyte-derived dendritic cells by reducing phosphorylation of inhibitory immune receptors Siglec-9 and Siglec-3. Experimental hematology 8 24882272
2014 Lectin-dependent localization of cell surface sialic acid-binding lectin Siglec-9. Cytotechnology 7 24449467
2010 A novel function of Siglec-9 A391C polymorphism on T cell receptor signaling. International archives of allergy and immunology 6 20733319
2025 Proximity Labeling and Genetic Screening Reveal that DSG2 is a Counter Receptor of Siglec-9 and Suppresses Macrophage Phagocytosis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 39813162
2024 Siglec-7 and Siglec-9 expression in primary triple negative and oestrogen receptor positive breast cancer and in vitro signalling. Clinical & translational immunology 5 39246414
2020 Synthetic Siglec-9 Agonists Inhibit Neutrophil Activation Associated with COVID-19. ChemRxiv : the preprint server for chemistry 5 33469569
2018 Mapping the interaction site and effect of the Siglec-9 inflammatory biomarker on human primary amine oxidase. Scientific reports 5 29391504
2025 Tumor-expressed GPNMB orchestrates Siglec-9+ TAM polarization and EMT to promote metastasis in triple-negative breast cancer. Proceedings of the National Academy of Sciences of the United States of America 4 40892920
2014 Enhanced lentiviral vector production in 293FT cells expressing Siglec-9. Cytotechnology 4 24464124
2024 Association of SIGLEC9 Expression with Cytokine Expression, Tumor Grading, KRAS, NRAS, BRAF, PIK3CA, AKT Gene Mutations, and MSI Status in Colorectal Cancer. Current issues in molecular biology 3 39727942
2023 The change of Siglec-9 expression in peripheral blood NK cells of SFTS patients can affect the function of NK cells. Immunology letters 3 37865296
2024 Effect of Hypoxia on Siglec-7 and Siglec-9 Receptors and Sialoglycan Ligands and Impact of Their Targeting on NK Cell Cytotoxicity. Pharmaceuticals (Basel, Switzerland) 2 39598355
2025 Sialylated glycoproteins bind to Siglec-9 in a cis manner on platelets to suppress platelet activation. Journal of thrombosis and haemostasis : JTH 1 40204021
2024 Transforming the Dark into Light: A Siglec-9 Switch. Cancer immunology research 1 39037058
2026 Chemoradiotherapy facilitates siglec-10+/siglec-9+ macrophage-mediated impairment of CD24+/MUC16+ tumor cell elimination and enhances PD-L2 dependent immunosuppression in cervical cancer. Cancer immunology, immunotherapy : CII 0 41801406
2026 Synthetic SIGLEC9-based chimeric switch receptor augments the efficacy of CAR macrophages against glioblastoma. Proceedings of the National Academy of Sciences of the United States of America 0 41843671
2025 [Preliminary study on the role of siglec-9 expression in peripheral blood of acute respiratory distress syndrome patients]. Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese journal of tuberculosis and respiratory diseases 0 39914835
2025 Rational design of FVIII sialylated peptides to target Siglec-3 and Siglec-9 and improve peptide formulations for reverse vaccines. Frontiers in bioengineering and biotechnology 0 40276034
2025 Soluble Siglec-9 Improves Intestinal Barrier Function in a Mouse Model of Metabolic Dysfunction-Associated Steatohepatitis. Metabolites 0 40559390
2025 Siglec-9 acts as an immune checkpoint marker on MDSCs in brucella infection. Frontiers in cellular and infection microbiology 0 41234517