{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T20:05:40Z","timestamp":1793649940981,"version":"4.5.1"},"reference-count":138,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T00:00:00Z","timestamp":1760572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Guanylate-binding protein 2 (GBP2) is an interferon-inducible GTPase that plays a critical role in innate immunity by defending against viral, bacterial, and parasitic infections through mechanisms such as furin inhibition and inflammasome activation. Beyond infectious disease, GBP2 demonstrates a context-dependent dual role in cancer\u2014acting as either a tumor suppressor or an oncogene by modulating key signaling pathways including JAK-STAT, Wnt\/\u03b2-catenin, and PI3K\/AKT\/mTOR. Its dysregulation is also increasingly implicated in autoimmune, neurological, and metabolic disorders, underscoring its promising utility as a diagnostic biomarker and therapeutic target. This review systematically synthesizes current knowledge on GBP2\u2019s structural features, biological functions, and functional duality. We further explore the paradoxical nature of its context-dependent roles and propose a unifying hypothesis to explain its dual functions, while outlining translational strategies to leverage GBP2\u2019s potential in biomarker development and targeted therapies.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1708319","type":"journal-article","created":{"date-parts":[[2025,10,16]],"date-time":"2025-10-16T05:32:29Z","timestamp":1760592749000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["From mechanisms to therapies: the multifaceted roles of guanylate-binding protein 2 in immunity, cancer, and beyond"],"prefix":"10.3389","volume":"16","author":[{"given":"Wenqi","family":"Cui","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianlu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1042\/BST20221500","article-title":"Guanylate-binding proteins in virus infection","volume":"51","author":"Chhabra","year":"2023","journal-title":"Biochem Soc Trans"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2023.07.002","article-title":"Guanylate-binding proteins: mechanisms of pattern recognition and antimicrobial functions","volume":"48","author":"Kirkby","year":"2023","journal-title":"Trends Biochem Sci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2005.25.435","article-title":"The guanylate-binding proteins (Gbps): proinflammatory cytokine-induced members of the dynamin superfamily with unique gtpase activity","volume":"25","author":"Vestal","year":"2005","journal-title":"J Interferon Cytokine Res"},{"key":"B4","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/s41389-021-00341-y","article-title":"Guanylate-binding proteins induce apoptosis of leukemia cells by regulating Mcl-1 and Bak","volume":"10","author":"Luo","year":"2021","journal-title":"Oncogenesis"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s00430-022-00736-7","article-title":"Functional cross-species conservation of Guanylate-Binding proteins in innate immunity","volume":"212","author":"Schelle","year":"2023","journal-title":"Med Microbiol Immunol"},{"key":"B6","article-title":"Gbp2 is a favorable prognostic marker of skin cutaneous melanoma and affects its progression via the Wnt\/Beta-catenin pathway","volume":"51","author":"Ji","year":"2021","journal-title":"Ann Clin Lab Sci"},{"key":"B7","doi-asserted-by":"publisher","first-page":"104689","DOI":"10.1016\/j.mvr.2024.104689","article-title":"Gbp2 inhibits pathological angiogenesis in the retina via the Akt\/Mtor\/Vegfa axis","volume":"154","author":"Xu","year":"2024","journal-title":"Microvasc Res"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2698","DOI":"10.1038\/s41467-024-46790-y","article-title":"Inos is necessary for Gbp-mediated T. 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