Authors

Zhengwei Wu , Zhenxun Wang , Seow Qi Ng , Jessica Alice 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 , Li Yieng Eunice Lau , Tony Kiat Hon Lim , Angela Takano , Eng Huat Tan , Anders Jacobsen Skanderup , Vinay Tergaonkar , Weiping Han , Ying Swan Ho , Daniel Shao Weng Tan , Wai Leong Tam

Abstract

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.

Read more at: https://doi.org/10.1016/j.cmet.2025.10.001