Exploring the role of sialidases in Galectin-1-associated resistance to cancer therapies.

The diverse repertoire of cell surface glycans, generated by the coordinated activity of glycosyltransferases and glycosidases, encodes critical biological information that is interpreted by glycan-binding proteins including galectins. Galectin-1 (GAL1), a member of this family, plays key roles across multiple hallmarks of cancer, including angiogenesis and immune evasion, driving resistance to anti-angiogenic and immunotherapeutic strategies through glycosylation-dependent mechanisms. Here, we first review the contribution of GAL1-glycan interactions to therapeutic resistance in cancer, with a particular focus on anti-angiogenic therapies and immunotherapy, and discuss the central role of glycosyltransferases in shaping these responses. While the biosynthesis of 'GAL1-permissive' glycans has been extensively characterized, the contribution of post-synthetic glycan remodeling to GAL1-driven therapeutic resistance remains uncertain. To explore mechanisms underlying GAL1-mediated resistance, we investigated whether tumor- or stromal-derived sialidases (NEU1 or NEU3) modulate sensitivity to vascular endothelial growth factor (VEGF)-targeted therapies by unmasking GAL1-binding glyco-epitopes. In the second part of the study, we present original in vivo experiments using gain- and loss-of-function approaches, demonstrating that, at least in our experimental settings, sialidases do not contribute to resistance to anti-VEGF treatment. Finally, bioinformatic analyses of patient datasets revealed differential regulation of GAL1, as well as specific glycosyltransferases, in patients responding or not to anti-VEGF or anti-PD-1 therapies. Collectively, these findings indicate that glycosyltransferases, particularly MGAT5, GCNT1, and ST6GAL1, coordinately shape the GAL1-specific glycome in settings of therapeutic resistance, whereas glycan remodeling by endogenous sialidases does not play a major role. Whether sialidases influence GAL1-dependent functions in other contexts remains to be explored.