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The shift includes reduced CD206-associated M2 marker expression and major metabolic remodeling: improved mitochondrial function, lower cellular cholesterol, and required reactive oxygen species production, leading to a re-educated secretome that suppresses hepatocellular carcinoma proliferation and 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outcomes are linked to the GDF11-driven macrophage changes?",{"text":72,"@type":64},"The re-educated secretome increases anti-tumoral cytokine and reactive oxygen species production, suppressing pro-proliferative and migratory capacity of hepatocellular carcinoma cells.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},362588,1790241195,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & 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[https://www.f6publishing.com](https://www.f6publishing.com) World J Gastroenterol 2026 March 14; 32(10): 115371  \nDOI: 10.3748/wjg.v32.i10.115371 ISSN 1007-9327 (print) ISSN 2219-2840 (online)  \nEDITORIAL  \nGrowth differentiation factor 11 reprograms M2-like macrophages: Targeting immunometabolism for cancer therapy  \nSaeed Mohammadi, Mahmoud Darweesh, Ahmed Al-Harrasi  \nProvenance and peer review:  \nInvited article; Externally peer reviewed.  \nPeer-review model: Single blind  \nPeer-review report’s classification Scientific Quality: Grade A, Grade B, Grade C, Grade C  \nNovelty: Grade A, Grade B, Grade C, Grade D  \nCreativity or Innovation: Grade A, Grade B, Grade C, Grade D Scientific Significance: Grade A, Grade C, Grade C, Grade D  \nP-Reviewer: Bouayad A, MD, Associate Professor, Morocco; Karatlı S, Academic Fellow, Türkiye; Kim JW, PhD, Assistant Professor, South Korea  \nReceived: October 16, 2025  \nRevised: November 13, 2025  \nAccepted: January 6, 2026  \nPublished online: March 14, 2026  \nProcessing time: 138 Days and 12.6 Hours  \n©Author(s) (or their employer(s))  \n2026. No commercial re-use. See Permissions. Published by Baishideng Publishing Group Inc.  \nSaeed Mohammadi, Mahmoud Darweesh, Ahmed Al-Harrasi, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Ad Dakhiliyah, Oman  \nORCID number: Saeed Mohammadi 0000-0001-9895-8468; Ahmed Al-Harrasi 0000-0003-0317- 8448.  \nCorresponding author: Ahmed Al-Harrasi, PhD, Professor, Natural and Medical Sciences Research Center, University of Nizwa, Birkat Al Mauz, PO Box 33, Nizwa 616, Ad Dakhiliyah, [Oman.](Oman. aharrasi@unizwa.edu.om)[ aharrasi@unizwa.edu.om](Oman. aharrasi@unizwa.edu.om)  \nAbstract  \nThis editorial comments on recent research by Escobedo-Calvario et al. Their study revealed that growth differentiation factor 11 (GDF11) functions as a potent, non-cytotoxic immunometabolic modulator within the tumor microenvironment. GDF11 treatment initiates an intense reprogramming in pro-tumoral M2-like macrophages by activating the Smad2/3 pathway and driving a fundamental shift in cellular identity. This reversal is highlighted by the significant downregulation of the M2 marker cluster of differentiation 206 and critical metabolic restructuring, including enhanced mitochondrial function (increased oxygen consumption rate), decreased total cellular cholesterol content, and a necessary increase in reactive oxygen species production. This work uniquely positions GDF11 as a dual-axis therapeutic agent, capable of both direct tumor inhibition and immunometabolic reprogramming of M2-like macrophages, yielding a re-educated secretome that effectively suppresses the pro-proliferative and migratory capacity of hepatocellular carcinoma cells. It suggests GDF11 may be a promising, mechanism-based therapeutic strategy for simultaneously managing the progression of a subset of malignancies and resolving the underlying chronic inflammatory and metabolic disorders associated with M2-like macrophage dysfunction.  \nKey Words: Growth differentiation factor 11; Macrophages; Immunometabolism; Macrophage polarization; Cancer; Tumor microenvironment; Hepatocellular carcinoma  \n [https://dx.doi.org/10.3748/wjg.v32.i10.115371](https://dx.doi.org/10.3748/wjg.v32.i10.115371) 1 March 14, 2026  Volume 32  Issue 10   \nMohammadi S et al. GDF11 shifts macrophage immunometabolism  \nCore Tip: Growth differentiation factor 11 (GDF11) is a potent immunometabolic modulator that can reprogram pro-tumoral M2-like macrophages primarily studied in hepatocellular carcinoma. GDF11 reverses their dysfunctional metabolic state by activating Smad2/3 signaling, restoring mitochondrial oxidative phosphorylation (as indicated by increased oxygen consumption rate), and reducing immunosuppressive cellular cholesterol. This critical metabolic shift induces the production of anti-tumoral cytokines","cbCail9Wa2Fr08rb","https://ap.wps.com/l/cbCail9Wa2Fr08rb","pdf",1137959,"English","# Abstract\n# Core Tip\n# Citation\n# Introduction","[{\"question\":\"What role does growth differentiation factor 11 (GDF11) play in the tumor microenvironment?\",\"answer\":\"GDF11 functions as a non-cytotoxic immunometabolic modulator that acts within the tumor microenvironment to reprogram pro-tumoral M2-like macrophages.\"},{\"question\":\"How does GDF11 reprogram M2-like macrophages mechanistically?\",\"answer\":\"GDF11 activates the Smad2/3 pathway, driving a shift in cellular identity and reducing M2 marker expression (including downregulation of CD206 cluster) alongside metabolic remodeling.\"},{\"question\":\"What functional outcomes are linked to the GDF11-driven macrophage changes?\",\"answer\":\"The re-educated secretome increases anti-tumoral cytokine and reactive oxygen species production, suppressing pro-proliferative and migratory capacity of hepatocellular carcinoma cells.\"}]","Growth differentiation factor 11 reprograms M2-like macrophages - Targeting immunometabolism for cancer therapy | PDF",1790148460]