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Metabolic imaging has been widely used to measure the early responses of tumors to treatment. Here, we assess the abilities of PET measurement of [ 18 F]FDG uptake and MRI measurement of hyperpolarized [1- 13 C]pyruvate metabolism to detect early changes in glycolysis following treatment-induced cell death in human colorectal (Colo205) and breast adenocarcinoma (MDA-MB-231) xenografts in mice. A TRAIL agonist that binds to human but not mouse cells induced tumor-selective cell death. Tumor glycolysis was assessed by injecting [1,6- 13 C 2 ]glucose and measuring 13 C-labeled metabolites in tumor extracts. Injection of hyperpolarized [1- 13 C]pyruvate induced rapid reduction in lactate labeling. This decrease, which correlated with an increase in histologic markers of cell death and preceded decrease in tumor volume, reflected reduced flux from glucose to lactate and decreased lactate concentration. However, [ 18 F]FDG uptake and phosphorylation were maintained following treatment, which has been attributed previously to increased [ 18 F]FDG uptake by infiltrating immune cells. Quantification of [ 18 F]FDG uptake in flow-sorted tumor and immune cells from disaggregated tumors identified CD11b + /CD45 + macrophages as the most [ 18 F]FDG-avid cell type present, yet they represented <5% of the cells present in the tumors and could not explain the failure of [ 18 F]FDG-PET to detect treatment response. MRI measurement of hyperpolarized [1- 13 C]pyruvate metabolism is therefore a more sensitive marker of the early decreases in glycolytic flux that occur following cell death than PET measurements of [ 18 F]FDG uptake. SIGNIFICANCE: These findings demonstrate superior sensitivity of MRI measurement of hyperpolarized [1- 13 C]pyruvate metabolism versus PET measurement of 18 F-FDG uptake for detecting early changes in glycolysis following treatment-induced tumor cell death., (©2019 American Association for Cancer Research.)