Induction of a metabolic switch from glucose to ketone metabolism programs ketogenic diet-induced therapeutic vulnerability in lung cancer

作者：Zhengwei Wu, Zhenxun Wang, Seow Q. Ng, Jessica A. Lidster, Paul Schwerd‐Kleine, Zi Jin Cheryl Phua, Kai Lay Esther Peh, Yin Ying Ho, Ju Yuan, S Shathishwaran, Xun Hui Yeo, Ying Zhang, Yui Hei Jasper Chiu, Lok Ting Lau, Tony Kiat Hon Lim, Angela Takano, Eng Huat Tan, Anders J. Skanderup, Vinay Tergaonkar, Weiping Han, Ying Swan Ho, Daniel S.W. Tan, Wai Leong Tam · 发表于：Cell Metabolism · 年份：2025 · DOI：10.1016/j.cmet.2025.10.001 · 被引用次数：3 · 研究领域：Diet and metabolism studies、Metabolism, Diabetes, and Cancer、Cancer, Hypoxia, and Metabolism

Tumor-initiating cells (TICs) preferentially reside in poorly vascularized, nutrient-stressed tumor regions, yet how they adapt to glucose limitation is unclear. We show that lung TICs, unlike bulk tumor cells, can switch from glucose to ketone utilization under glucose deprivation. Ex vivo ketone supplementation or a prolonged ketogenic diet supports TIC growth and tumor-initiating capacity. Integrated metabolomics, genomics, and flux analyses reveal that ketones fuel ketolysis, fatty acid synthesis, and de novo lipogenesis. Paradoxically, ketogenic diet intervention creates metabolic vulnerabilities in TICs, sensitizing them toward inhibition of the ketone transporter monocarboxylate transporter 1 (MCT1), regulated by its chaperone protein CD147, as well as toward pharmacological blockade of fatty acid synthase (FASN). Loss of CD147 ablates TICs under glucose limitation conditions in vitro and in vivo . These findings uncover a nutrient-responsive metabolic switch in lung TICs and provide mechanistic insight into how dietary manipulation can influence cancer progression and enhance the efficacy of targeted therapies. • Lung TICs switch from glucose to ketone metabolism to overcome nutrient stress • Ketones fuel ketolysis and lipogenesis to promote tumor initiation and growth • Ketogenic diet induces a dependency on MCT1-CD147-mediated ketone transport • MCT1 inhibition under ketogenic conditions impairs TIC function and tumor growth Zhengwei et al. show that lung tumor-init...