Huang HY, Tian L. Kill two birds with one stone: Reprogramming tumor microenvironment with growth differentiation factor 11. World J Gastroenterol 2026; 32(9): 115259 [PMID: 41810435 DOI: 10.3748/wjg.v32.i9.115259]
Corresponding Author of This Article
Lin Tian, Assistant Professor, Principal Investigator, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangdong Provincial Clinical Research Center for Cancer, No. 651 Dongfeng East Road, Guangzhou 500060, Guangdong Province, China. tianlin@sysucc.org.cn
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Immunology
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letter
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Huang HY, Tian L. Kill two birds with one stone: Reprogramming tumor microenvironment with growth differentiation factor 11. World J Gastroenterol 2026; 32(9): 115259 [PMID: 41810435 DOI: 10.3748/wjg.v32.i9.115259]
World J Gastroenterol. Mar 7, 2026; 32(9): 115259 Published online Mar 7, 2026. doi: 10.3748/wjg.v32.i9.115259
Kill two birds with one stone: Reprogramming tumor microenvironment with growth differentiation factor 11
Han-Ying Huang, Lin Tian
Han-Ying Huang, Lin Tian, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou 500060, Guangdong Province, China
Author contributions: Huang HY and Tian L was responsible for conceptualization, preparing, reviewing and editing the manuscript.
Supported by National Natural Science Foundation of China, No. 82173278 and No. 82573221; Young Talents Program of SYSUCC, No. YTP-SYSUCC-0045; and Fostering Program for NSFC Young Applicants (Tulip Talent Training Program) of SYSUCC, No. TTP-SYSUCC-202406.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
Corresponding author: Lin Tian, Assistant Professor, Principal Investigator, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangdong Provincial Clinical Research Center for Cancer, No. 651 Dongfeng East Road, Guangzhou 500060, Guangdong Province, China. tianlin@sysucc.org.cn
Received: October 15, 2025 Revised: November 22, 2025 Accepted: January 4, 2026 Published online: March 7, 2026 Processing time: 137 Days and 23 Hours
Abstract
A major driver of hepatocellular carcinoma (HCC)’s aggressiveness is its ability to hijack the immune system, specifically by recruiting immunosuppressive tumor-associated macrophages. These M2-type macrophages are coerced into promoting tumor growth and metastasis. This study by Escobedo-Calvario et al reveals that the protein growth differentiation factor 11 can effectively “re-educate” these pro-tumoral macrophages by reducing classic M2 markers, rewiring cellular metabolism, and boosting production of reactive oxygen species, which ultimately switch the macrophages from a pro-tumor state toward an anti-tumor state. When applied to HCC cells, growth differentiation factor 11 also reduced the cancer cells’ capacity to proliferate and migrate – key hallmarks of deadly metastasis. This two-pronged attack could represent a groundbreaking strategy to enhance current immunotherapies and control the aggressiveness of HCC, offering new hope for future treatments.
Core Tip: This preview summarizes the dual function of Growth Differentiation Factor 11 (GDF11) as a novel strategy against hepatocellular carcinoma. Beyond suppressing cancer cells, GDF11 uniquely "re-educates" pro-tumoral M2 macrophages – a key driver of immunosuppression. It reprograms these cells by reducing the immunosuppressive marker CD206, rewiring their metabolism, and boosting reactive oxygen species. This shifts the macrophages to an anti-tumor state, neutralizing their cancer-promoting effects. By simultaneously targeting the tumor and its microenvironment, GDF11 offers a novel approach to break immunotherapy resistance, positioning it as a promising candidate for future combination therapies.
