European journal of pharmacologyOct 25, 2025

Incretin signals linking metabolism, inflammation, and tumor growth in people with obesity

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 2, 2026

Abstract

GLP-1 receptor activation has shown antiproliferative effects in gastrointestinal adenocarcinomas and pancreatic ductal adenocarcinoma models.

Preclinical studies in rodents indicate that GLP-1 receptor activation may affect thyroid C-cells and pancreatic ducts.
Human studies have produced inconsistent signals regarding cancer risk associated with GLP-1 receptor agonists.
GIP receptor activation often stimulates pathways that enhance tumor proliferation in colorectal and neuroendocrine cancers.
GLP-1 receptor stimulation can promote growth in certain neuroendocrine tumors, highlighting tissue-specific signaling effects.
GLP-1 receptor agonists may influence the tumor microenvironment by reducing inflammation and altering stromal activity.
Current clinical evidence suggests no overall increase in cancer risk with GLP-1 receptor agonist therapy, though caution is recommended in specific patient populations.

Simplified

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.

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Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

PubMed

Incretin signals linking metabolism, inflammation, and tumor growth in people with obesity

Abstract

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