Targeting Siglec–Sialylated MUC1 Immune Axis in Cancer

Siglecs play a key role in mediating cell–cell interactions via the recognition of different sialylated glycoconjugates, including tumor-associated MUC1, which can lead to the activation or inhibition of the immune response. The activation occurs through the signaling of Siglecs with the cytoplasmic immunoreceptor tyrosine-based activation motif (ITAM)-containing proteins, while the inhibition signal is a result of the interaction of intracellular immunoreceptor tyrosine-based inhibition motif (ITIM)-bearing receptors. The interaction of tumor-associated MUC1 sialylated glycans with Siglecs via ITIM motifs decreases antitumor immunity. Consequently, these interactions are expected to play a key role in tumor evasion. Efforts to modulate the response of immune cells by blocking the immune-suppressive effects of inhibitory Siglecs, driving immune-activating Siglecs, and/or altering the synthesis and expression of the sialic acid glycocalyx are new therapeutic strategies deserving further investigation. We will highlight the role of Siglec’s family receptors in immune evasion through interactions with glycan ligands in their natural context, presented on the protein such as MUC1, factors affecting their fine binding specificities, such as the role of multivalency either at the ligand or receptor side, their spatial organization, and finally the current and future therapeutic interventions targeting the Siglec–sialylated MUC1 immune axis in cancer.