Multifaceted Roles of Guanylate-Binding Proteins in Cancer
Abstract
1. Structure, Function, and Roles of GBPs in Immunity
2. GBPs in Cancer: Context-Dependent Roles in Tumor Progression
2.1. Molecular Mechanisms of GBPs in Tumorigenesis and Therapy Resistance
2.1.1. Immune Modulation
2.1.2. Treatment Resistance
2.1.3. Metastasis
2.2. GBPs as Biomarkers for Cancer Prognosis and Treatment Response
3. Therapeutic Targeting of GBPs: Challenges and Opportunities
Future Directions and Unanswered Questions
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Cancer Type | Promoting or Suppressing Cancer | Mechanisms | Ref |
---|---|---|---|
Renal Cancer | GBP1/GBP2/GBP4: Promoting | GBP1: Enhances growth and metastasis via EGFR signaling and actin remodeling. GBP2: Facilitates immune evasion and Stat3-driven invasion. GBP4: Enhances tumor resilience via Golgi/plasma membrane localization. | [15,25,26,27,28] |
Lung Adenocarcinoma | GBP1: Promoting | Binds beta-tubulin to boost motility and metastasis to lymph nodes, bones, or brain via GTPase activity. | [18] |
Ovarian Cancer | GBP1: Promoting; GBP4/GBP5: Suppressing | GBP1: Protects from paclitaxel via beta-tubulin/IDO-1, enhancing drug resistance. GBP4: Supports immune responses. GBP5: Promotes immune infiltration. | [19,21,22,28,29,30] |
Glioblastoma | GBP1/GBP2/GBP3/GBP5: Promoting | GBP1: EGFR-induced effector, drives actin remodeling and matrix degradation. GBP2: Facilitates immune evasion and Stat3-driven invasion. GBP3: Activates p62-ERK1/2 and MGMT-mediated DNA repair. GBP5: Activates Src/ERK1/2/MMP3 signaling. | [16,17,31,32,33,34] |
Colorectal Cancer | GBP1/GBP2/GBP5: Suppressing | GBP1: Enhances immune recognition via IFN-γ. GBP2: Inhibits Wnt signaling, enhances paclitaxel sensitivity. GBP5: Supports immune infiltration. | [23,29,35] |
Breast Cancer | GBP1: Dual (Suppressing in IFN-driven, Promoting in growth factor-driven); GBP2: Suppressing | GBP1: Suppresses growth in IFN-driven cancers; promotes brain metastasis via T lymphocytes in growth factor-driven cancers. GBP2: Inhibits growth via Drp-1/ATG2, suppresses PI3K/AKT/mTOR, and sensitizes to paclitaxel. | [3,36,37,38,39,40] |
Melanoma | GBP1/GBP2: Suppressing | GBP1: Enhances immune surveillance and IFN-γ-induced T cell infiltration. GBP2: Inhibits Wnt/β-catenin pathway. | [24,41,42] |
Pancreatic Adenocarcinoma | GBP2: Promoting | Enhances survival and metastasis in hypoxic, acidic TME as an acidosis-related signature. | [26,43] |
Esophageal Squamous Cell Carcinoma | GBP1/GBP2: Promoting | GBP1: Promotes lymph node metastasis and poor prognosis via enhanced invasion and migration. GBP2: A p53-regulated target gene to promote tumor growth. | [44,45] |
Endometrial Cancer | GBP5: Suppressing | Supports immune infiltration. | [29,30,34,46,47,48] |
Stomach Cancer | GBP5: Promoting | Drives JAK1-STAT1/GBP5/CXCL8 feedback loop. | [48] |
Oral Squamous Cell Carcinoma | GBP6: Potential Suppressing | Reduced expression; potential diagnostic marker. | [49,50] |
Head and Neck Squamous Cell Carcinoma (HNSCC) | GBP1/GBP2/GBP7: Suppressing | Low expression correlates with shorter survival; linked to immune regulation and vesicle localization. | [51,52] |
GBP | Cancer Type | Function in TME Interaction | Key Mechanisms | Ref |
---|---|---|---|---|
GBP1 | Colorectal Cancer | Enhances immune activation | Recruits effector cells (macrophages, dendritic cells, T lymphocytes) via LPS-like recognition of tumor debris; driven by gastrointestinal expression and IFN-γ responses. | [23] |
GBP2 | Breast Cancer | Boosts immune sensitivity | Promotes autophagy via ATG2, inhibiting PI3K/AKT/mTOR signaling; enhances immune cell infiltration (e.g., CD8+ T cells) through homodimerization and cytokine regulation. | [38,61] |
GBP2 | Osteosarcoma | Enhances immune cell infiltration | Promotes CD8+ T cell infiltration to suppress tumor growth; driven by homodimerization and cytokine regulation. | [38,61] |
GBP4 | Pancreatic Ductal Carcinoma (PDAC) | Promotes tumor progression | Overexpressed due to DNA hypomethylation; increases infiltration of exhausted CD8+ T cells, supporting tumor growth. | [58] |
GBP4 | Melanoma | Enhances immune checkpoint responses | Modulates TME dynamics to support anti-EGFR therapy; linked to Golgi and plasma membrane localization. | [62,63] |
GBP4 | Non-Small Cell Lung Cancer (NSCLC) | Supports anti-EGFR therapy | Enhances immune checkpoint responses; linked to Golgi and plasma membrane localization. | [62,63] |
GBP5 | Lung Cancer (NSCLC, SCLC) | Enhances immune cell infiltration | Increases infiltration of B cells, CD4+ and CD8+ T cells, and NK cells; sensitizes tumors to PD-L1 blockade via Golgi localization and IFN-γ-driven immune checkpoint modulation. | [59] |
GBP5 | Ovarian Cancer | Impairs immune efficacy | Mutations reduce T cell function and increase PD-L1 expression, promoting tumor escape. | [30] |
GBP5 | Non-Small Cell Lung Cancer (NSCLC) | Associated with favorable prognosis | Upregulated in tumor tissues; correlates with immune-related gene expression (e.g., PD-L1), enhancing anti-PD-1/PD-L1 therapy efficacy. | [60] |
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Ahmetoglu, D.; Zheng, H.; Swart, A.; Zhu, H.; Li, M. Multifaceted Roles of Guanylate-Binding Proteins in Cancer. Int. J. Mol. Sci. 2025, 26, 5477. https://doi.org/10.3390/ijms26125477
Ahmetoglu D, Zheng H, Swart A, Zhu H, Li M. Multifaceted Roles of Guanylate-Binding Proteins in Cancer. International Journal of Molecular Sciences. 2025; 26(12):5477. https://doi.org/10.3390/ijms26125477
Chicago/Turabian StyleAhmetoglu, Derin, Haoyi Zheng, Aaron Swart, Hua Zhu, and Ming Li. 2025. "Multifaceted Roles of Guanylate-Binding Proteins in Cancer" International Journal of Molecular Sciences 26, no. 12: 5477. https://doi.org/10.3390/ijms26125477
APA StyleAhmetoglu, D., Zheng, H., Swart, A., Zhu, H., & Li, M. (2025). Multifaceted Roles of Guanylate-Binding Proteins in Cancer. International Journal of Molecular Sciences, 26(12), 5477. https://doi.org/10.3390/ijms26125477