{
  "abstract": "Immune checkpoints are key regulators of the immune system that cancer cells exploit to evade immune surveillance. While these pathways have been targeted with antibody therapies such as PD-1/PD-L1 inhibitors, other inhibitory receptors, like sialic acid-binding immunoglobulin-type lectins (Siglecs), remain clinically underexplored. Among the many Siglecs on immune cells that interact with sialosides on cancer cells, Siglec-9 and Siglec-10 are prominently expressed on macrophages within the tumor microenvironment, functioning as key inhibitory immune checkpoints that suppress macrophage-mediated phagocytosis and cytotoxicity. Similarly, Siglec-7 and Siglec-9 are expressed on NK cells, acting as primary immune checkpoints that inhibit cellular cytotoxicity. Since all Siglecs recognize sialic acids, we sought to identify a common small-molecule inhibitor to target these receptors for immunotherapy. We first chemoenzymatically synthesized more than 60 glycans, including multiantennary glycans with terminal sialic acids, and assembled them onto a glycan microarray to screen for high-affinity binders to these Siglecs. We identified several strong binders in these array assays; among them, a truncated glycolyl sialoside (R3) was found to strongly inhibit the interaction of Siglec-10 with HER2-low MCF-7 cells, substantially enhancing macrophage-mediated phagocytosis and cytotoxicity. Notably, R3 also interacts significantly with other inhibitory immune checkpoint receptors, including Siglec-5, -7, -9, -11, and -15, thereby relieving Siglec-mediated suppression and enhancing NK cell-mediated cytotoxicity in cell-based assays. Structural studies are underway to investigate the binding mode of R3 with these Siglecs to guide further optimization toward a common small-molecule inhibitor targeting multiple inhibitory glyco-immune checkpoints for cancer immunotherapy.",
  "abstract_shown": true,
  "affiliations": [
    "Genomics Research Center, Academia Sinica, 128 Academia Rd., Sec, 2, Taipei11529, Taiwan.",
    "Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, California92037, United States."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Cinya Chung"
    },
    {
      "affs": [
        1
      ],
      "name": "Ruofan Li",
      "orcid": "0000-0001-8060-897X"
    },
    {
      "affs": [
        0
      ],
      "name": "Li-Chun Cheng",
      "orcid": "0000-0001-6187-288X"
    },
    {
      "affs": [
        0
      ],
      "name": "Chen-Yo Fan"
    },
    {
      "affs": [
        0
      ],
      "name": "Kuo-Shiang Liao",
      "orcid": "0009-0007-3039-7570"
    },
    {
      "affs": [
        0
      ],
      "name": "Chih-Chuan Kung"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Chi-Huey Wong",
      "orcid": "0000-0002-9961-7865"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0z0n57y8gaamv.bib",
  "cited_by": 0,
  "doi": "10.1021/jacs.6c15475",
  "fulltext_url": "https://europepmc.org/articles/PMC13674246",
  "id": "0z0n57y8gaamv",
  "issns": [
    "0002-7863",
    "1520-5126"
  ],
  "landing_url": "https://europepmc.org/article/MED/42913558",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Glycosylation and Glycoproteins Research"
    ]
  ],
  "openalex": "W7214725873",
  "pdf_url": "https://europepmc.org/articles/PMC13674246?pdf=render",
  "pmcid": "PMC13674246",
  "pmid": "42913558",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/0z0n57y8gaamv.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:14Z",
      "native_id": "MED:42913558",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42913558"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Glycosylation and Glycoproteins Research",
      "subfield": "molecular-biology"
    }
  ],
  "title": "A Common Small-Molecule Inhibitor Targeting Multiple Siglecs Associated with Immune Checkpoint Suppression of Cytotoxicity and Phagocytosis.",
  "title_text": "A Common Small-Molecule Inhibitor Targeting Multiple Siglecs Associated with Immune Checkpoint Suppression of Cytotoxicity and Phagocytosis.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:14Z",
  "url": "https://research.draconitic.com/paper/0z0n57y8gaamv",
  "venue": "Journal of the American Chemical Society",
  "versions": []
}