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

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

  • Cell Metab. 2025 Oct 24:S1550-4131(25)00435-8. doi: 10.1016/j.cmet.2025.10.001.
Zhengwei Wu 1,  Zhenxun Wang 2,  Seow Qi Ng 3,  Jessica Alice Lidster 1,  Paul Schwerd-Kleine 4,  Zi Jin Cheryl Phua 5,  Kai Lay Esther Peh 6,  Yin Ying Ho 6,  Ju Yuan 5,  S Shathishwaran 5,  Xun Hui Yeo 1,  Ying Zhang 5,  Yui Hei Jasper Chiu 5,  Li Yieng Eunice Lau 3,  Tony Kiat Hon Lim 7,  Angela Takano 7,  Eng Huat Tan 8,  Anders Jacobsen Skanderup 5,  Vinay Tergaonkar 9,  Weiping Han 10,  Ying Swan Ho 11,  Daniel Shao Weng Tan 12,  Wai Leong Tam 13
Affiliations

Affiliations

  • 1 Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A(∗)STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore.
  • 2 Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A(∗)STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore; Centre for Vision Research, Duke NUS Medical School, 8 College Rd, Singapore 169857, Singapore; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore 169856, Singapore.
  • 3 Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A(∗)STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore.
  • 4 Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A(∗)STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore; Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Feodor-Lynen Straße 25, Munich 81377, Germany.
  • 5 Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A(∗)STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore.
  • 6 Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A(∗)STAR), 20 Biopolis Way, Singapore 138668, Singapore.
  • 7 Department of Anatomical Pathology, Singapore General Hospital, Singapore 169608, Singapore.
  • 8 Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
  • 9 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Singapore 138673, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, 14 Medical Drive, Singapore 117599, Singapore.
  • 10 Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A(∗)STAR), 61 Biopolis Drive, Singapore 138673, Singapore.
  • 11 Bioprocessing Technology Institute (BTI), Agency for Science, Technology and Research (A(∗)STAR), 20 Biopolis Way, Singapore 138668, Singapore; Food, Chemical and Biotechnology Cluster, Singapore Institute of Technology, 1 Punggol Coast Road, Singapore 828608, Singapore.
  • 12 Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A(∗)STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore; Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
  • 13 Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A(∗)STAR), 60 Biopolis Street, Genome, Singapore 138672, Singapore; Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, Singapore 117597, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University Singapore, 14 Medical Drive, Singapore 117599, Singapore. Electronic address: tamwl@a-star.edu.sg.
PMID: 41138721 DOI: 10.1016/j.cmet.2025.10.001
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.

Keywords

CD147; MCT1; glucose stress; ketogenic diet; ketone metabolism; lung cancer; metabolic reprogramming; monocarboxylate transporter; tumor-initiating cells.

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