GAL1 Becomes A New Anticancer Target
On June 10, 2025, Diego O. Croci, Gabriel A. Rabinovich, and others from the Institute of Biology and Experimental Medicine (IBYME) and the Institute of Histology and Embryology of Mendoza (IHEM) in Argentina published an article titled "Glycosylation-driven programs coordinate immunoregulatory and pro-angiogenic functions of myeloid-derived suppressor cells" in Immunity. This study found that the glycosylation-dependent GAL1 signaling pathway is crucial for MDSCs to simultaneously exert both immunosuppressive and pro-angiogenic functions. GAL1 recognizes specific glycans and activates the CD11b-CD18-CD177 complex and the STAT3 pathway, synergistically driving the dual "accomplice" effects of MDSCs. Blocking the GAL1-glycan interaction significantly impairs MDSC function and inhibits tumor progression, providing a new target for tumor immunotherapy and anti-angiogenic therapies.
Myeloid-derived suppressor cells (MDSCs) drive tumor progression by suppressing antitumor immunity and promoting angiogenesis, but the molecular link between these two processes remains unclear. This study reveals that a glycosylation-dependent program driven by Galectin-1 (GAL1) simultaneously confers immunosuppressive and proangiogenic functions to MDSCs, mediated through a shared receptor signaling pathway.
GAL1 expression is associated with an enhanced MDSC phenotype and poor prognosis in multiple human cancers. Analysis of mono- and polymorphic MDSCs in tumor-bearing mice reveals that glycan signatures within specific microenvironments determine GAL1's selective binding. Through glycosylation-dependent interactions with the CD18-CD11b-CD177 receptor complex and STAT3 signaling, GAL1 coordinately regulates the immunosuppressive and proangiogenic programs of MDSCs, thereby driving tumor growth in vivo. Myeloid cell-specific knockout of β-galactosyl α(2,6)-sialyltransferase 1 (preventing α(2,6)-sialic acid modification) enhances GAL1-driven regulatory circuits and accelerates tumor progression, while GAL1-neutralizing antibodies can mitigate these effects. Therefore, targeting GAL1-glycan interactions may provide new opportunities for Reprogramming MDSCs and improving the efficacy of immunotherapy and anti-angiogenic therapies.
Fig. 1 Glycosylation-driven programs coordinate immunoregulatory and pro-angiogenic functions of myeloid-derived suppressor cells. (Blidner, et al. 2025)
MDSCs are a type of myeloid cell that highly proliferates in tumors and chronic inflammatory environments. They have multifaceted functions, primarily manifesting in: inhibiting the cytotoxicity of effector T cells; inducing the formation of regulatory T cells (Tregs); secreting immunosuppressive factors (such as IL-10 and TGF-β1); expressing immune checkpoint molecules such as PD-L1; and promoting tumor angiogenesis, helping tumors obtain nutrients.
Thus, MDSCs not only directly promote tumor progression but also serve as a key source of resistance to immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs.
Although MDSCs possess the dual capabilities of immunosuppression and angiogenesis, how these two pathways are simultaneously regulated remains a mystery. Previous studies have focused on metabolic factors, such as the fatty acid transporter FATP2; transcriptional regulation, such as the KDM6B demethylase; and cellular stress, such as hypoxia and endoplasmic reticulum stress. However, these mechanisms often explain only a single function, lacking a core molecule that oversees their dual roles.
Glycan Modification is one of the most important information encoding systems on the cell surface. Different glycan structures act like "barcodes," which, when decoded by glycan-binding proteins, can trigger distinct signaling pathways. Extensive evidence indicates that glycan remodeling is closely linked to tumor immune evasion, and that members of the galectin family (such as GAL1) can regulate the functions of various cell types, including immune cells and endothelial cells, by recognizing specific glycans.
Based on these clues, the research team proposed a core hypothesis: Could MDSCs simultaneously achieve immunosuppression and angiogenesis through the glycosylation-dependent GAL1 signaling pathway?
The study first discovered in clinical samples that high GAL1 expression is closely associated with poor prognosis in various cancers and is accompanied by enhanced MDSC function. Further experiments revealed that in tumor-bearing mice, different MDSC subtypes (monocytic and granulocytic) possess specific Glycan signatures within different tissue microenvironments; these glycan signatures determine GAL1's selective binding and signaling activation.
In other words, the glycan composition of MDSCs acts like a switch for GAL1, determining whether they can be activated as dual-function accomplices.
Further mechanistic studies revealed that GAL1 triggers the downstream STAT3 signaling pathway by interacting with the CD11b-CD18 (αMβ2 integrin)-CD177 complex on the surface of MDSCs.
STAT3 is a core transcription factor that induces both the immunosuppressive and pro-angiogenic phenotypes of MDSCs. Upon GAL1 binding, MDSCs experience elevated levels of ROS, NO, and ARG1, along with increased expression of immune checkpoint molecules (PD-L1, VISTA, and IDO1). Furthermore, GAL1 stimulates MDSCs to secrete factors such as VEGF, enhancing their pro-angiogenic capacity.
This reveals a complete chain of events: glycan characteristics, GAL1 binding, receptor activation, STAT3 signaling, and MDSC functional upgrades.
Further research has revealed that an increased ratio of core O-glycans (core-2 O-glycans) to branched N-glycans (β1,6-branched N-glycans) makes MDSCs more susceptible to GAL1 binding. Extended LacNAc residues provide more recognition sites for GAL1. Although MDSCs have high levels of α(2,6)-sialylation, the overall glycan environment still favors a "GAL1-susceptible" profile.
This explains why tumor-associated MDSCs are more susceptible to GAL1 activation than MDSCs in the spleen or periphery.
In Mouse Models, the research team knocked out β-galactosidase α(2,6)-sialyltransferase 1 in myeloid cells, resulting in MDSCs being more susceptible to GAL1 activation and accelerated tumor growth. However, when a neutralizing GAL1 antibody was used, these effects were significantly alleviated, weakening both the immunosuppressive and angiogenic abilities of MDSCs and inhibiting tumor growth.
This result strongly demonstrates that the GAL1-glycan axis is a key driver of the tumor-promoting function of MDSCs and a potential therapeutic target.
Traditional immune checkpoint therapies (such as PD-1/PD-L1 antibodies) primarily target T cells, while MDSCs, as a significant source of immunosuppression, often become the root cause of resistance to ICI therapy. This study establishes the GAL1-glycan interaction as a new myeloid glycan checkpoint, providing a potential solution for addressing the shortcomings of existing therapies. The study also suggests that factors upregulated by GAL1 (such as AREG, ANGPT1, and ENG) are not only involved in angiogenesis but also associated with fibrosis, suggesting that GAL1 may be a core regulatory molecule in the immunosuppression-angiogenesis-fibrosis trinity.
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