Nutrition exerts profound effects on health and dietary interventions are commonly used to treat diseases of metabolic etiology. Although cancer has a substantial metabolic component, the principles that define whether nutrition may be used to influence tumour outcome are unclear. Nevertheless, it is established that targeting metabolic pathways with pharmacological agents or radiation can sometimes lead to controlled therapeutic outcomes. In contrast, whether specific dietary interventions could influence the metabolic pathways that are targeted in standard cancer therapies is not known. We now show that dietary restriction of methionine (MR), an essential amino acid, and the reduction of which has aging and obesogenic properties, influences cancer outcome through controlled and reproducible changes to one carbon metabolism. This pathway metabolizes methionine and further is the target of a host of cancer interventions involving chemotherapy and radiation. MR produced therapeutic responses in chemoresistant RAS-driven colorectal cancer patient derived xenografts and autochthonous KRAS G12D+/-;TP53 -/--driven soft tissue sarcomas resistant to radiation. Metabolomics revealed the therapeutic mechanisms to occur through tumor cell autonomous effects on the flux through one carbon metabolism that impacted redox and nucleotide metabolism, thus interacting with the antimetabolite or radiation intervention. Finally, in a controlled and tolerated feeding study in humans, MR resulted in similar effects on systemic metabolism as obtained in responsive mice. These findings provide 2 evidence that a targeted dietary manipulation can affect specific tumor cell metabolism to mediate broad aspects of cancer outcome. MainThe dietary intake of nutrients, and ultimately the levels of circulating metabolites that provide nutrients to tumors are determined by a manifestation of complex physiological processes occurring in liver, gut, pancreas, brain, and other tissues. While it is known that changes in the growth media that cancer cells encounter in culture can have dramatic effects on cell metabolism and cell fate 1-3 , the extent to which dietary nutrient availability, which is the corresponding situation in vivo, can alter metabolic pathways in tumors and affect therapeutic outcomes in cancer is largely unknown. Recent studies [4][5][6] have shown that the restriction of amino acids, serine and glycine, can modulate cancer outcome in xenotransplanted and autochthonous tumor models. The availability of histidine and asparagine appears to mediate the response of cancer cells to methotrexate 7 and the progression of breast cancer metastasis 8 , respectively. Whether such interventions broadly affect metabolism or have targeted effects on specific pathways related to these nutrients is unknown. One intriguing possibility for a specific dietary intervention in cancer is the restriction of methionine, an essential amino acid in one carbon metabolism. Methionine is the most variable metabolite found in human plasma 9 , has a myriad of ...