Glycosylation-driven programs coordinate immunoregulatory and pro-angiogenic functions of myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) promote tumor progression by suppressing antitumor immunity and inducing angiogenesis; however, the mechanisms linking these processes remain uncertain. Here, we identified a glycosylation-dependent program driven by galectin-1 (GAL1) that imparted both immunoregulatory and pro-angiogenic functions to MDSCs through shared receptor signaling pathways. GAL1 expression was associated with enhanced MDSC phenotypes and poor prognosis in diverse human cancers. Analysis of monocytic and polymorphonuclear MDSCs from tumor-bearing mice revealed niche-specific glycan signatures that selectively regulated GAL1 binding. Through glycosylation-dependent interactions with the CD18-CD11b-CD177 receptor complex and STAT3 signaling, GAL1 simultaneously orchestrated immunosuppressive and pro-angiogenic programs in MDSCs, driving tumor growth in vivo. Myeloid-specific deletion of β-galactoside α(2,6)-sialyltransferase 1, which prevented α(2,6)-linked sialic acid incorporation, enhanced GAL1-driven regulatory circuits and accelerated tumor progression, effects that were mitigated by GAL1-neutralizing antibodies. Thus, targeting GAL1-glycan interactions may offer opportunities to reprogram MDSCs and enhance the efficacy of immunotherapeutic and anti-angiogenic strategies.