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Reducing metabolic stress within the tumor microenvironment (TME) could be essential for improving the efficacy of cancer immunotherapy. Using a mouse model of melanoma, we show here that appropriately timed treatment with the PPARα agonist fenofibrate improves the ability of a T cell–inducing cancer vaccine to delay tumor progression. Fenofibrate reduced the use of glucose by tumor and stromal cells in the TME and promoted the use of fatty acids for their metabolic needs. The glucose within the TME was in turn available for use by vaccine-induced tumor-infiltrating CD8+ T cells, which improved their ability to slow tumor progression. Early fenofibrate treatment 3 days after vaccination improved functions of circulating CD8+ T cells but failed to significantly affect tumor-infiltrating lymphocyte (TIL) metabolism or decrease tumor progression. In contrast, delaying treatment until day 5 after vaccination modified TIL metabolism and augmented the vaccine's ability to slow tumor progression. In summary, our findings reveal that a PPARα agonist can increase the efficacy of a cancer vaccine by reprogramming cells within tumors to increase fatty acid metabolism, providing T cells access to glucose in the TME. Significance: These findings suggest that metabolic manipulations using already approved drugs may offer an easy pathway to increase the efficacy of vaccines against solid tumors.

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