Rewiring PD-1/PD-L1 combination therapy via glyco-immune targeting of galectins: Toward clinical translation

Despite advances in PD-1/PD-L1 combination therapies, clinical benefits remain limited and toxicity is significant. Galectins, a family of β-galactoside-binding lectins, have emerged as mechanistically distinct, multimodal targets with the potential to address these limitations. By modulating glycan-protein networks in the tumor microenvironment, galectin inhibition alleviates T cell exclusion, immune exhaustion, immunosuppressive cell activation, and steric blockade of PD-(L)1 antibodies. Several galectin inhibitors (e.g., GR-MD-02, GB1211, LYT-200) are under clinical evaluation. Early trials showing encouraging efficacy-toxicity profiles and some combinations received FDA Fast Track designations. This review summarizes mechanistic and clinical advances and highlights their translational implications for galectin-targeted combination therapies.