A Sialic Acid-Caged Generic Platform for Sialoengineering of Tumors with Artificial Immuno-Ligand

Selective glycoengineering of tumors in vivo is a highly promising strategy for tumor treatment. Although metabolic glycan labeling using precursors of sialic acid (Sia) is an effective method for attaching chemical probes to cell surfaces, it often lacks specificity for tumors. Herein, we report a tumor-activated sialoengineering approach utilizing Sia with C1-carboxylate caged with lysine (K). Probe decaging by carboxypeptidase in tumors enables tumor-exofacial expression of abiotic Sia tolerating differing C9-substitutions such as azide (AzSia) and m-phenoxybenzamide (PBASia). Notably, PBASia acts as a high-affinity ligand for the CD22 receptor of B cells. Treatment with PBASia-K leads to robust suppression of subcutaneous B16-F10 tumors in mice. These data show the potential of C1-caged Sia to function as a generic small-molecule platform for in vivo sialoengineering of tumor cells, allowing for the generation of cell surface-anchored C9-substituted Sia that could be harnessed to stimulate an anti-tumor response.