Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, delivering robust metabolic and cardiovascular benefits. However, their potential impact on tumori Show more
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type 2 diabetes and obesity, delivering robust metabolic and cardiovascular benefits. However, their potential impact on tumorigenesis remains debated. Preclinical findings in rodents have suggested that GLP-1R activation may influence thyroid C-cells and pancreatic ducts, while human studies have yielded inconsistent cancer risk signals. This review synthesizes current evidence on GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling in cancer biology, emphasizing the role of biased agonism and context-dependent effects. GLP-1R activation, predominantly via cAMP/PKA signaling, has shown antiproliferative effects in gastrointestinal adenocarcinomas and pancreatic ductal adenocarcinoma models, whereas GIPR activation frequently engages PI3K/Akt (PI3K, phosphoinositide 3-kinase; Akt, protein kinase B) and ERK/MAPK cascades (ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase), enhancing proliferation in colorectal and neuroendocrine tumors. Conversely, GLP-1R stimulation can promote growth in GLP-1R-high neuroendocrine tumors, reflecting ligand- and tissue-specific signaling biases. Beyond direct tumor cell effects, GLP-1RAs modulate the tumor microenvironment by reducing NF-κB-driven inflammation, altering stromal activity, and potentially enhancing immune surveillance. Current clinical evidence does not support a generalized increase in cancer risk with GLP-1RA therapy; benefits in metabolic control may even reduce obesity-related cancer incidence. Nonetheless, caution is advised in patients with medullary thyroid carcinoma, MEN2, or GLP-1R-high neuroendocrine tumors. The emerging paradigm suggests precision approaches, integrating receptor profiling, biased agonist design, and risk stratification, will be key to safely leveraging incretin-based therapies in oncology. Show less