A study reveals that targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. Tumors contain both oxygenated and hypoxic regions, with hypoxic cells relying on glycolysis and lactate production, while oxygenated cells use oxidative metabolism. Lactate, previously considered a waste product, is now shown to be a key substrate for oxidative metabolism in oxygenated tumor cells. This creates a metabolic symbiosis between glycolytic and oxidative tumor cells. Monocarboxylate transporter 1 (MCT1) is identified as the main pathway for lactate uptake by a human cervix squamous carcinoma cell line that uses lactate for oxidative metabolism. Inhibiting MCT1 with α-cyano-4-hydroxycinnamate (CHC) or siRNA switches cells from lactate-fueled respiration to glycolysis. In mouse models of lung carcinoma and human colorectal adenocarcinoma, CHC induced this switch, leading to reduced tumor growth as hypoxic/glycolytic cells died from glucose starvation and remaining cells became sensitive to irradiation. MCT1 is expressed in various primary human tumors, suggesting clinical potential for MCT1 inhibition as an anticancer treatment. The study also shows that MCT1 inhibition radiosensitizes tumors by increasing tumor oxygenation and reducing hypoxia. MCT1 is expressed in multiple human tumor cell lines and primary tumors, including breast, head and neck, and lung cancers. The findings highlight the importance of MCT1 in tumor metabolism and suggest that targeting MCT1 could be a promising therapeutic strategy for cancer treatment.A study reveals that targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. Tumors contain both oxygenated and hypoxic regions, with hypoxic cells relying on glycolysis and lactate production, while oxygenated cells use oxidative metabolism. Lactate, previously considered a waste product, is now shown to be a key substrate for oxidative metabolism in oxygenated tumor cells. This creates a metabolic symbiosis between glycolytic and oxidative tumor cells. Monocarboxylate transporter 1 (MCT1) is identified as the main pathway for lactate uptake by a human cervix squamous carcinoma cell line that uses lactate for oxidative metabolism. Inhibiting MCT1 with α-cyano-4-hydroxycinnamate (CHC) or siRNA switches cells from lactate-fueled respiration to glycolysis. In mouse models of lung carcinoma and human colorectal adenocarcinoma, CHC induced this switch, leading to reduced tumor growth as hypoxic/glycolytic cells died from glucose starvation and remaining cells became sensitive to irradiation. MCT1 is expressed in various primary human tumors, suggesting clinical potential for MCT1 inhibition as an anticancer treatment. The study also shows that MCT1 inhibition radiosensitizes tumors by increasing tumor oxygenation and reducing hypoxia. MCT1 is expressed in multiple human tumor cell lines and primary tumors, including breast, head and neck, and lung cancers. The findings highlight the importance of MCT1 in tumor metabolism and suggest that targeting MCT1 could be a promising therapeutic strategy for cancer treatment.