GLP-1 signaling in tumor metabolism and immunity: mechanisms and strategies

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for diabetes, are now recognized to exert context-dependent effects on tumor metabolism and immunity. Here, we synthesize emerging evidence that GLP-1R signaling remodels cancer bioenergetics by reversing the Warburg effect, restoring mitochondrial function, and modulating glutamine and autophagy pathways, thereby constraining metabolic plasticity. In parallel, GLP-1RAs enhance cytotoxic T cell and natural killer (NK) cell activity, reshape macrophage polarization, and suppress myeloid-derived suppressor cells, collectively alleviating immunosuppression. However, these actions vary markedly across tumor types: prostate, liver, and colorectal cancers exhibit clear benefits, whereas breast and thyroid cancers reveal paradoxical responses, highlighting the influence of molecular subtypes, oncogenic mutations, and microenvironmental cues. Safety remains a concern, particularly regarding thyroid malignancy, although large-scale cohorts suggest an overall favorable risk–benefit balance. We propose that multi-omics biomarker discovery, innovative trial designs, and next-generation GLP-1 analogs or peptide–drug conjugates will be critical to refine patient stratification and unlock the therapeutic promise of GLP-1RAs in oncology.