A preserved TGFβ cytostatic response through DLD-mediated metabolic modulation undermines anti-TGFβ therapy in gastric cancer
Despite the well-known role of the transforming growth factor-β (TGFβ) pathway in cancer progression, therapies targeting it have largely failed in the clinic. This suggests our understanding of TGFβ's function is incomplete. Here we show that this therapeutic failure is rooted in a fundamental paradox: while TGFβ promotes malignant traits in gastric cancer, many cancer cells remain sensitive to its potent tumor-suppressive effects. We uncover that this suppression works by impairing the cell's energy metabolism through modulating dihydrolipoamide dehydrogenase (DLD). Therefore, broadly blocking the TGFβ pathway can inadvertently release a natural brake on tumor growth. Based on this insight, we demonstrate that co-targeting this metabolic vulnerability with an inhibitor (devimistat) alongside an anti-TGFβ agent significantly enhances therapeutic efficacy in gastric cancer models. This combination approach presents a promising strategy to overcome the limitations of current therapies.
Authors
- Zexian Liu (ORCID: https://orcid.org/0000-0001-9698-0610)
- Hai‐long Piao (ORCID: https://orcid.org/0000-0001-7451-0386)
- Zerong Cai (ORCID: https://orcid.org/0000-0002-4514-7116)
- Zhao-Lei Zeng (ORCID: https://orcid.org/0000-0003-4420-5625)
- Xin‐Yuan Guan (ORCID: https://orcid.org/0000-0002-4485-6017)
- Huai‐Qiang Ju (ORCID: https://orcid.org/0000-0003-1713-5465)
- Yongqiang Zheng (ORCID: https://orcid.org/0000-0003-3246-2800)
- Kun Lun Liao (ORCID: https://orcid.org/0000-0002-2949-8215)
- Wenqi Chen (ORCID: https://orcid.org/0000-0002-1953-8383)
- Qi‐Nian Wu (ORCID: https://orcid.org/0000-0002-9771-9956)
- X M Zhang (ORCID: https://orcid.org/0009-0004-6687-4680)
- Yi Han (ORCID: https://orcid.org/0009-0004-0687-4945)
- Tian Tian (ORCID: https://orcid.org/0000-0001-6570-8104)
- Huan Chen (ORCID: https://orcid.org/0000-0002-5089-2719)
- Yue Chen (ORCID: https://orcid.org/0000-0002-1763-1461)
- Yanyu Zhang (ORCID: https://orcid.org/0000-0001-8992-1719)
- Yun Li (ORCID: https://orcid.org/0000-0003-4097-2392)
- Yi‐Qian Pan (ORCID: https://orcid.org/0009-0003-2516-2778)
- Rui‐Hua Xu (ORCID: https://orcid.org/0000-0001-9771-8534)
- Haoxiang Wu
- Zheng-Yu Qian
- Tingting Wang (ORCID: https://orcid.org/0000-0003-1689-7257)
Institutions
- Sun Yat-sen University (CN)
- Jinan University (CN)
- Dalian Institute of Chemical Physics (CN)
- Chinese Academy of Sciences (CN)
- Nanfang Hospital (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- Southern Medical University (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1038/s41467-025-64997-5
- Citations
- 1
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.94
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- China Postdoctoral Science Foundation
- Sanming Project of Medicine in Shenzhen
- National Key Research and Development Program of China
- Sun Yat-sen University Cancer Center
- Basic and Applied Basic Research Foundation of Guangdong Province