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

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-initiating cells (TICs) adapt to glucose limitation by switching to ketone utilization, dependent on MCT1 and its chaperone CD147. The ketogenic diet expands the TIC pool yet, paradoxically, induces vulnerability toward MCT1 inhibition, demonstrating how dietary intervention may be exploited to enhance anti-cancer therapies.