Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and therapies targeting glucose-dependent insulinotropic polypeptide (GIP) have demonstrated efficacy in the treatment of type 2 diabetes (T2D) and obesity. GLP-1 and GIP are collectively referred to as incretins. The strong epidemiological link between T2D/obesity and cancer risk suggests that GLP-1 and GIP may serve a substantial role in tumor metabolism. The effects of incretin hormones and the counter-regulatory hormone glucagon (GCG) on tumor biology may have important implications for understanding tumor microenvironmental regulation and for informing cancer therapy. The present review summarizes the mechanisms by which these hormones influence the tumor microenvironment. Beyond the fundamental biology of incretins and GCG, the present review details how GLP-1RAs regulate immune cell functions, including the functions of T cells, neutrophils, natural killer cells and macrophages, to foster an antitumor immune microenvironment. Furthermore, the present review explores their roles in tumor metabolic reprogramming, affecting tumor cell cycle progression, extracellular matrix remodeling and mitochondrial function. Although preclinical and clinical data suggest that GLP-1RAs can reduce the incidence and progression of certain obesity-related cancer types, such as pancreatic and liver cancer, their impact on other malignancies, such as breast and endometrial cancer, remains controversial, with GLP-1RAs potentially exhibiting context-dependent pro-tumor effects. However, based on current evidence, the benefits of incretin hormones and GCG in cancer therapy appear to outweigh the risks. The present review suggests that targeting incretin and GCG signaling holds considerable promise in oncology, but necessitates a deeper mechanistic understanding and more careful patient stratification to fully harness its clinical utility while minimizing potential risks.