Galectins are a family of ß-galactoside-binding proteins that play a variety of roles in normal physiology. In cancer, their expression levels are typically elevated and often associated with poor prognosis. They are known to fuel a variety of cancer progression pathways through their glycan-binding interactions with cancer, stromal, and immune cell surfaces. Of the 15 galectins in mammals, galectin (Gal)-1, -3, and -9 are particularly notable for their critical roles in tumor immune escape. While these galectins play integral roles in promoting cancer progression, they are also instrumental in regulating the survival, differentiation, and function of anti-tumor T cells that compromise anti-tumor immunity and weaken novel immunotherapies. To this end, there has been a surge in the development of new strategies to inhibit their pro-malignancy characteristics, particularly in reversing tumor immunosuppression through galectin–glycan ligand-targeting methods. This review examines some new approaches to evading Gal-1, -3, and -9–ligand interactions to interfere with their tumor-promoting and immunoregulating activities. Whether using neutralizing antibodies, synthetic peptides, glyco-metabolic modifiers, competitive inhibitors, vaccines, gene editing, exo-glycan modification, or chimeric antigen receptor (CAR)-T cells, these methods offer new hope of synergizing their inhibitory effects with current immunotherapeutic methods and yielding highly effective, durable responses.

Chimeric antigen receptor (CAR)-T cell therapy has demonstrated remarkable efficacy in hematologic malignancies; however, durable responses remain limited by tumor microenvironment (TME)-mediated immunosuppression. Galectin-3 (Gal-3), a β-galactoside-binding lectin enriched in the TME, contributes to CAR-T cell dysfunction by impairing cytotoxicity, promoting apoptosis, and altering cellular signaling. While we previously demonstrated that enforced expression of the α2,6 sialyltransferase ST6GAL1 reduces galectin binding and improves CAR-T cell function, the mechanistic basis underlying this protection remains unclear. Here, we report that Gal-3 induced a hypometabolic state in CAR-T cells characterized by reduced mitochondrial function, ATP production, and glucose utilization. In contrast, ST6GAL1-overexpressing CAR-T cells preserved metabolic fitness and functional resilience under Gal-3 stress. Additionally, Gal-3 rewired cytokine signaling by increasing IL-5 expression and dysregulating downstream pathways, whereas enforced ST6GAL1 expressing CAR-T cells exhibited increased SOCS1 and SOCS3 expression and attenuated STAT5 activation. Transcriptomic analysis of CAR-T cells from diffuse large B-cell lymphoma patients further revealed enrichment of STAT5-associated signaling and SOCS1 expression in complete responders compared to partial responders. Collectively, these findings identify glycoengineering as a promising strategy to enhance CAR-T cell persistence and function under Gal-3-mediated immunosuppressive stress.