Galectins at the crossroads of tumor immunity, metabolism, and metastasis: mechanisms, therapeutic resistance, and translational opportunities.

Galectins, a structurally conserved family of β-galactoside-binding lectins, have emerged as key regulators of cancer progression. However, their integrated roles across tumor immunity, metabolic rewiring, and metastasis have yet to be fully defined. In this review, we synthesize current evidence on major galectin family members, particularly galectin (Gal)-1, Gal-3, Gal-4, Gal-7, Gal-9, and Gal-13, and delineate how they drive tumor progression through mechanistically distinct yet convergent pathways. Specifically, galectins induce T-cell dysfunction through T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)- and programmed cell death protein 1 (PD-1)-associated signaling, reprogram macrophages and myeloid-derived suppressor cells (MDSCs) via phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and nuclear factor kappa B (NF-κB) pathways, and modulate innate immune effectors, including natural killer (NK) cells, neutrophils, and dendritic cells, in a context-dependent manner. Beyond immune regulation, galectins reshape tumor metabolism through effects on glycolysis, lipid metabolism, and glycan remodeling, and differentially regulate ferroptosis susceptibility, with the contrasting roles of Gal-1 and Gal-13 underscoring functional diversity within the family. Emerging evidence further implicates galectins in resistance to chemotherapy, targeted therapy, immune checkpoint blockade, and chimeric antigen receptor T-cell (CAR-T) therapy, positioning them as candidate therapeutic targets. We also discuss galectin-directed strategies, including small-molecule inhibitors, nanomedicine-based platforms, vaccination approaches, and rational combination therapies, and highlight the promise of multi-galectin biomarker panels for precision oncology.