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

  • Authors:
    • Min Hu
    • Chang-Jun Jiang
    • Cheng Yi
  • View Affiliations / Copyright

    Affiliations: Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China, College of Health and Intelligent Engineering, Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China, Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
    Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 183
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    Published online on: May 8, 2026
       https://doi.org/10.3892/etm.2026.13178
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Abstract

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.
View Figures

Figure 1

Core signaling pathways of GLP-1, GIP
and GCG. GLP-1 and GIP enhance glucose-dependent insulin secretion
in pancreatic β-cells via Gs-mediated cAMP production, which
activates downstream PKA and Epac signaling linked to secretory
responses and survival-associated signaling. GCG activates hepatic
glucose production and fatty acid oxidation by engaging both
Gs/cAMP/PKA and Gq/IP3/Ca2+ pathways in hepatocytes.
cAMP signaling produces distinct cell-specific physiological
outputs, including hormone secretion and survival-associated
signaling in pancreatic isleT cells. Created with Figdraw.com. AC, adenylate cyclase; AMPK,
AMP-activated protein kinase; CaMKII,
Ca2+/calmodulin-dependent protein kinase II; CREB,
cAMP-response element-binding protein; DAG, diacylglycerol; Epac,
exchange protein directly activated by cAMP; ERK, extracellular
signal-regulated kinase; F1,6BP, fructose 1,6-bisphosphate; F6P,
fructose 6-phosphate; FASN, fatty acid synthase; G6Pase,
glucose-6-phosphatase; GCG, glucagon; GCGR, glucagon receptor; GIP,
glucose-dependent insulinotropic polypeptide; GIPR,
glucose-dependent insulinotropic polypeptide receptor; GLP-1,
glucagon-like peptide-1; GLP-1R, glucagon-like peptide-1 receptor;
GPK, glycogen phosphorylase kinase; GS, glycogen synthase; INS,
insulin; IP3, inositol 1,4,5-trisphosphate; IP3R, inositol
1,4,5-trisphosphate receptor; IRS-2, insulin receptor substrate 2;
PEPCK, phosphoenolpyruvate carboxykinase; PFK-1,
phosphofructokinase-1; PIP2, phosphatidylinositol 4,5-bisphosphate;
PIP3, phosphatidylinositol 3,4,5-trisphosphate; PKA, protein kinase
A; PKC, protein kinase C; PLC, phospholipase C; Rab3, Ras-related
protein Rab-3A; SUR1, sulfonylurea receptor 1; VD Ca2+
channel, voltage-dependent Ca2+ channel.

Figure 2

Modulation of the tumor immune
microenvironment by GLP-1RAs. GLP-1RAs promote a shift from an
immunosuppressive tumor microenvironment towards a more
immunoresponsive state. Mechanistically, this is reflected by
reduced neutrophil extracellular trap formation and ROS-associated
immunosuppression, enhanced NK cell-mediated tumor lysis, promotion
of DC maturation and antigen presentation, modulation of T-cell
activity, and context-dependent regulation of macrophage
polarization. Collectively, these effects support antitumor
immunity by improving immune cell function and alleviating
immunosuppressive signaling within the tumor microenvironment.
Created with Figdraw.com. DC, dendritic cell;
GLP-1RA, glucagon-like peptide-1 receptor agonist; MHC, major
histocompatibility complex; NET, neutrophil extracellular trap; NK,
natural killer; ROS, reactive oxygen species; Treg, regulatory T
cell.

Figure 3

Multifaceted impact of GLP-1RAs on
tumor metabolic reprogramming. GLP-1RAs influence three
interconnected processes relevant to tumor-associated metabolic
reprogramming. In tumor cells, they are shown to suppress
proliferation, induce cell-cycle arrest or apoptosis, and promote
autophagy in selected preclinical models. In the extracellular
matrix, they attenuate profibrotic ECM remodeling and
fibrosis-associated signaling, including reductions in
collagen/fibronectin-related deposition and profibrotic marker
expression. In mitochondria, they improve mitochondrial function by
enhancing Ca2+-dependent mitochondrial activity,
preserving mitochondrial membrane potential, reducing oxidative
stress and apoptosis, and promoting mitochondrial quality-control
signaling. Created with Figdraw.com.
α-SMA, α-smooth muscle actin; Δψm, mitochondrial membrane
potential; ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein
kinase; Bace2, β-site APP-cleaving enzyme 2; BC, breast cancer;
BNIP3, BCL2 interacting protein 3; CAT, catalase; CREB,
cAMP-response element-binding protein; CSPG, chondroitin sulfate
proteoglycan; DOX, doxorubicin; ECM, extracellular matrix; Exe-4,
exendin-4; FN, fibronectin; GLP-1, glucagon-like peptide-1; GLP-1R,
glucagon-like peptide-1 receptor; GLP-1RA, glucagon-like peptide-1
receptor agonist; Has1, hyaluronan synthase 1; HCC, hepatocellular
carcinoma; HG, high glucose; HL, high lipid; HMC, human mesangial
cells; Hpse, heparanase; HSC, hepatic stellate cell; Hspg2, heparan
sulfate proteoglycan 2; IAPP, islet amyloid polypeptide; IV-Col,
type IV collagen; MASLD, metabolic dysfunction-associated steatotic
liver disease; miR, microRNA; p-, phosphorylated; PC, prostate
cancer; PGC-1α, peroxisome proliferator-activated receptor γ
coactivator-1α; PINK1, PTEN-induced kinase 1; PKA, protein kinase
A; PPARγ, peroxisome proliferator-activated receptor γ; ROS,
reactive oxygen species; Sdc4, syndecan-4; SKP2, S-phase
kinase-associated protein 2; UCP2, uncoupling protein 2.
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Copy and paste a formatted citation
Spandidos Publications style
Hu M, Jiang C and Yi C: Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review). Exp Ther Med 32: 183, 2026.
APA
Hu, M., Jiang, C., & Yi, C. (2026). Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review). Experimental and Therapeutic Medicine, 32, 183. https://doi.org/10.3892/etm.2026.13178
MLA
Hu, M., Jiang, C., Yi, C."Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review)". Experimental and Therapeutic Medicine 32.1 (2026): 183.
Chicago
Hu, M., Jiang, C., Yi, C."Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review)". Experimental and Therapeutic Medicine 32, no. 1 (2026): 183. https://doi.org/10.3892/etm.2026.13178
Copy and paste a formatted citation
x
Spandidos Publications style
Hu M, Jiang C and Yi C: Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review). Exp Ther Med 32: 183, 2026.
APA
Hu, M., Jiang, C., & Yi, C. (2026). Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review). Experimental and Therapeutic Medicine, 32, 183. https://doi.org/10.3892/etm.2026.13178
MLA
Hu, M., Jiang, C., Yi, C."Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review)". Experimental and Therapeutic Medicine 32.1 (2026): 183.
Chicago
Hu, M., Jiang, C., Yi, C."Modulation of the tumor microenvironment by incretins and glucagon: Metabolic and immune mechanisms (Review)". Experimental and Therapeutic Medicine 32, no. 1 (2026): 183. https://doi.org/10.3892/etm.2026.13178
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