Galectins are glycan-binding proteins that contain one or two carbohydrate domains and mediate multiple biological functions. By analyzing clinical tumor samples, the abnormal expression of galectins is known to be linked to the development, progression and metastasis of cancers. Galectins also have diverse functions on different immune cells that either promote inflammation or dampen T cell-mediated immune responses, depending on cognate receptors on target cells. Thus, tumor-derived galectins can have bifunctional effects on tumor and immune cells. This review focuses on the biological effects of galectin-1, galectin-3 and galectin-9 in various cancers and discusses anticancer therapies that target these molecules.

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Galectin-9 is a risk gene in inflammatory bowel disease. By transcriptomic analyses of ileal biopsies and PBMCs from inflammatory bowel disease patients, we identified a positive correlation between galectin-9 expression and colitis severity. We observed that galectin-9–deficient T cells were less able to induce T cell–mediated colitis. However, several mouse-based studies reported that galectin-9 treatment induces T cell apoptosis and ameliorates autoimmune diseases in an exogenously modulated manner, indicating a complicated regulation of galectin-9 in T cells. We found that galectin-9 is expressed mainly inside T cells, and its secreted form is barely detected under physiological conditions. Endogenous galectin-9 was recruited to immune synapses upon T cell activation. Moreover, proximal TCR signaling was impaired in galectin-9–deficient T cells, and proliferation of these cells was decreased through an intracellularly modulated manner. Th17 cell differentiation was downregulated in galectin-9–deficient T cells, and this impairment can be rescued by strong TCR signaling. Taken together, these findings suggest that intracellular galectin-9 is a positive regulator of T cell activation and modulates the pathogenesis of autoimmune diseases.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, with unfavorable prognosis and 5-year survival. The purpose of this study was to investigate the underlying mechanisms involved in TNBC progression. We determined that CD24 expression was elevated in highly lung and lymph node metastatic TNBC cells. CD24 depletion inhibited primary tumor growth and lymph node and lung metastasis and reduced the number of blood and lymphatic vessels in the tumor microenvironment. CD24 knockdown impaired EGFR/Met-mediated signaling and reduced lymphangiogenesis-and angiogenesis-related molecules, including vascular endothelial growth factors A and C, by promoting EGFR and Met protein instability via the lysosomal degradation pathway. CD24 monoclonal antibody treatment reduced lung metastasis and prolonged the survival in a lung metastasis mouse model. Clinical analyses revealed that the CD24 high /MET high "double-positive" signature identified a subset of TNBC patients with worst outcomes. We conclude that CD24 could be a therapeutic target by itself and in combination with the Met expression could be a good prognostic biomarker for TNBC patients.