This study investigates how TRAF6, an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates the development of CD8 T cell memory after infection by modulating fatty acid metabolism. CD8 T cells play a crucial role in immunity against infection and cancer, undergoing a developmental program that includes expansion, contraction, and the persistence of long-lived memory cells. The study shows that TRAF6-deficient CD8 T cells have a defect in generating memory cells, characterized by the disappearance of antigen-specific cells after primary immunization. Microarray analyses revealed altered expression of genes regulating fatty acid metabolism in TRAF6-deficient CD8 T cells. Activated TRAF6-deficient CD8 T cells showed defective AMP-activated kinase activation and mitochondrial fatty acid oxidation in response to growth factor withdrawal. Administration of metformin, an anti-diabetic drug, restored fatty acid oxidation and CD8 T cell memory generation in the absence of TRAF6. Metformin also increased CD8 T memory cells in wild-type mice, improving the efficacy of an experimental anti-cancer vaccine. The study shows that TRAF6 is crucial for CD8 T cell memory development, but not for effector cell responses. TRAF6-deficient CD8 T cells fail to generate memory cells due to defects in fatty acid metabolism, which can be corrected by metformin. The study also shows that TRAF6-deficient CD8 T cells are unable to survive contraction and persist as long-lived memory cells due to an inability to properly engage pathways of fatty acid oxidation when growth factors become limiting after the peak of the immune response. Metformin treatment promotes survival of TRAF6-deficient CD8 T cells and enhances memory cell generation, resulting in greater protective immunity. The study highlights the importance of fatty acid metabolism in CD8 T cell memory development and suggests that pharmacological modulation of this metabolic pathway could be a potential target for vaccine design.This study investigates how TRAF6, an adaptor protein in the TNF-receptor and interleukin-1R/Toll-like receptor superfamily, regulates the development of CD8 T cell memory after infection by modulating fatty acid metabolism. CD8 T cells play a crucial role in immunity against infection and cancer, undergoing a developmental program that includes expansion, contraction, and the persistence of long-lived memory cells. The study shows that TRAF6-deficient CD8 T cells have a defect in generating memory cells, characterized by the disappearance of antigen-specific cells after primary immunization. Microarray analyses revealed altered expression of genes regulating fatty acid metabolism in TRAF6-deficient CD8 T cells. Activated TRAF6-deficient CD8 T cells showed defective AMP-activated kinase activation and mitochondrial fatty acid oxidation in response to growth factor withdrawal. Administration of metformin, an anti-diabetic drug, restored fatty acid oxidation and CD8 T cell memory generation in the absence of TRAF6. Metformin also increased CD8 T memory cells in wild-type mice, improving the efficacy of an experimental anti-cancer vaccine. The study shows that TRAF6 is crucial for CD8 T cell memory development, but not for effector cell responses. TRAF6-deficient CD8 T cells fail to generate memory cells due to defects in fatty acid metabolism, which can be corrected by metformin. The study also shows that TRAF6-deficient CD8 T cells are unable to survive contraction and persist as long-lived memory cells due to an inability to properly engage pathways of fatty acid oxidation when growth factors become limiting after the peak of the immune response. Metformin treatment promotes survival of TRAF6-deficient CD8 T cells and enhances memory cell generation, resulting in greater protective immunity. The study highlights the importance of fatty acid metabolism in CD8 T cell memory development and suggests that pharmacological modulation of this metabolic pathway could be a potential target for vaccine design.