Mohammadi S, Darweesh M, Al-Harrasi A. Growth differentiation factor 11 reprograms M2-like macrophages: Targeting immunometabolism for cancer therapy. World J Gastroenterol 2026; 32(10): 115371 [DOI: 10.3748/wjg.v32.i10.115371]
Corresponding Author of This Article
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. aharrasi@unizwa.edu.om
Research Domain of This Article
Immunology
Article-Type of This Article
Editorial
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Mar 14, 2026; 32(10): 115371 Published online Mar 14, 2026. doi: 10.3748/wjg.v32.i10.115371
Growth differentiation factor 11 reprograms M2-like macrophages: Targeting immunometabolism for cancer therapy
Saeed Mohammadi, Mahmoud Darweesh, Ahmed Al-Harrasi
Saeed Mohammadi, Mahmoud Darweesh, Ahmed Al-Harrasi, Natural and Medical Sciences Research Center, University of Nizwa, Nizwa 616, Ad Dakhiliyah, Oman
Author contributions: Mohammadi S was responsible for the conceptualization, investigation, and writing of the original draft; Darweesh M contributed to the study design, conducted the literature review, prepared the illustrations, and performed writing, review and editing; Al-Harrasi A provided supervision, and contributed to writing, review and editing.
Supported by the Oman Ministry of Higher Education, Research, and Innovation, No. BFP/RGP/HSS/24/015.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Corresponding 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. aharrasi@unizwa.edu.om
Received: October 16, 2025 Revised: November 13, 2025 Accepted: January 6, 2026 Published online: March 14, 2026 Processing time: 138 Days and 12.9 Hours
Abstract
This 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.
Core 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 and reactive oxygen species, neutralizing tumor cell proliferation and migration. GDF11 could be a promising, mechanism-based strategy to flip the immune-suppressive microenvironment toward tumor destruction.
