Hypoxic tumor cells use primarily glycolysis for energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. Although lactate is generally considered as a waste product, we show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. In the tumor symbiont, preference for lactate by oxidative cells renders glucose available for glycolytic cells. This exquisite cooperation can be disrupted therapeutically: inhibition of monocarboxylate transporter 1 (MCT1), that we identified as the prominent path for lactate uptake, induces a switch from lactate-fueled respiration to glycolysis in oxygenated tumor cells. As a consequence, hypoxic/glycolytic tumor cells die from glucose starvation, and the remaining oxidative cells may be targeted by radiotherapy. Validation of this new therapeutic strategy using three different tumor models and MCT1 expression in an array of primary human tumors provide clinical significance to anticancer MCT1 inhibition.

*Supported by NIH grants CA40355, CA91565, CA56690, and CA125618, by an Action de Recherche Concertée (ARC 04/09-317) from the Communauté Française de Belgique, and by the J. Maisin and St Luc Foundations. O.F. is a Senior Research Associate of the Fonds National de la Recherche Scientifique (FNRS). P.S. is a FNRS Research Associate, and was supported by the Belgian American Educational Foundation (BAEF) and by the Fonds Spéciaux de la Recherche (UCL).