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Life sciences · Journal article
Journal of the American Chemical Society · September 29, 2026
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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.