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<p>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.</p>

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A preserved TGFβ cytostatic response through DLD-mediated metabolic modulation undermines anti-TGFβ therapy in gastric cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月14日

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  • Yi-Qian Pan,
  • Yi Han,
  • Zheng-Yu Qian,
  • Xin-Yao Zhang,
  • Ting-Ting Wang,
  • Ze-Rong Cai,
  • Huan Chen,
  • Yun Li,
  • Kun Liao,
  • Yong-Qiang Zheng,
  • Yan-Yu Zhang,
  • Qi-Nian Wu,
  • Hao-Xiang Wu,
  • Tian Tian,
  • Wenqi Chen,
  • Yue Chen,
  • Zhao-Lei Zeng,
  • Ze-Xian Liu,
  • Hai-Long Piao,
  • Xin-Yuan Guan,
  • Rui-Hua Xu,
  • Huai-Qiang Ju

摘要

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.