2026-10-14T07:22:57Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34027273 2026-09-29T18:20:53Z category_1 category_4 category_146 category_8 category_19 category_873 category_46 category_64 category_128 category_132 category_134 portal_63 item_type_6 month_year_09_2026

A Common Small-Molecule Inhibitor Targeting Multiple Siglecs Associated with Immune Checkpoint Suppression of Cytotoxicity and Phagocytosis Cinya Chung (1945402) Ruofan Li (1568194) Li-Chun Cheng (5956934) Chen-Yo Fan (8275146) Kuo-Shiang Liao (5075381) Chih-Chuan Kung (20931194) Chi-Huey Wong (63704) Biophysics Biochemistry Space Science Microbiology Pharmacology Chemical Sciences not elsewhere classified Immunology Cancer Hematology Infectious Diseases Virology truncated glycolyl sialoside terminal sialic acids like sialic acid first chemoenzymatically synthesized evade immune surveillance substantially enhancing macrophage primary immune checkpoints immune checkpoint suppression including multiantennary glycans phagocytosis immune checkpoints cancer cells exploit enhancing nk cell thereby relieving siglec inhibit cellular cytotoxicity immune checkpoints immune cells nk cells immune system cancer cells suppress macrophage strongly inhibit mediated suppression 60 glycans mediated phagocytosis type lectins tumor microenvironment structural studies optimization toward molecule inhibitor macrophages within low mcf l1 inhibitors key regulators glycan microarray common small binding mode binding immunoglobulin based assays array assays antibody therapies affinity binders 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. 2026-09-29T00:00:00Z Text Journal contribution 10.1021/jacs.6c15475.s001 https://figshare.com/articles/journal_contribution/A_Common_Small-Molecule_Inhibitor_Targeting_Multiple_Siglecs_Associated_with_Immune_Checkpoint_Suppression_of_Cytotoxicity_and_Phagocytosis/34027273 CC BY-NC 4.0