The unprecedented clinical efficacy of immune checkpoint inhibitors heralds new hope for many cancer patients. However, existing inhibitors predominantly target the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PDL-1) pathway, which accounts for dysfunctional immunity in less than 40% of human solid tumors. Therefore, these inhibitors are inefficacious in many cancers. Accordingly, a critical gap exists for alternative immune checkpoint inhibitors to treat these recalcitrant cancers. Ample evidence indicates that other cellular pathways, such as the sialoglycan-Siglec pathway, compromise anti-tumor immunity. We present a novel small molecule (UMBZ1) that attenuated the sialoglycan-Siglec interaction, restoring natural killer (NK) cells’ ability to kill cancer cells in vitro. Also, in vitro, UMBZ1 was not cytotoxic to the cancer cells but primed the NK cells to kill the cancer cells. This molecule will likely expand the frontiers of immune checkpoint immunotherapy to small molecules, which are amenable for oral and transdermal delivery.

Blockading the sialoglycan-siglec immune checkpoint axis for cancer immunotherapy

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