The study investigates the role of TRAF6 in the development of CD8 T-cell memory. CD8 T cells play a crucial role in immunity and cancer, and their memory formation involves a developmental program that includes expansion, contraction, and the persistence of long-lived memory (T_M) cells. The researchers found that TRAF6, an adaptor protein, regulates CD8 T_M-cell development by modulating fatty acid metabolism. Mice lacking TRAF6 had robust effector (T_E) cell responses but failed to generate T_M cells, characterized by the disappearance of antigen-specific cells weeks after primary immunization. Microarray analysis revealed altered expression of genes regulating fatty acid metabolism in TRAF6-deficient CD8 T cells. Activated CD8 T cells lacking TRAF6 showed defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and T_M-cell generation in TRAF6-deficient mice. This treatment also increased T_E cells in wild-type mice and improved the efficacy of an experimental anti-cancer vaccine. The study highlights the importance of FAO in T_M-cell development and suggests that pharmacological modulation of T-cell metabolism could enhance vaccine efficacy.The study investigates the role of TRAF6 in the development of CD8 T-cell memory. CD8 T cells play a crucial role in immunity and cancer, and their memory formation involves a developmental program that includes expansion, contraction, and the persistence of long-lived memory (T_M) cells. The researchers found that TRAF6, an adaptor protein, regulates CD8 T_M-cell development by modulating fatty acid metabolism. Mice lacking TRAF6 had robust effector (T_E) cell responses but failed to generate T_M cells, characterized by the disappearance of antigen-specific cells weeks after primary immunization. Microarray analysis revealed altered expression of genes regulating fatty acid metabolism in TRAF6-deficient CD8 T cells. Activated CD8 T cells lacking TRAF6 showed defective AMP-activated kinase activation and mitochondrial fatty acid oxidation (FAO) in response to growth factor withdrawal. Administration of the anti-diabetic drug metformin restored FAO and T_M-cell generation in TRAF6-deficient mice. This treatment also increased T_E cells in wild-type mice and improved the efficacy of an experimental anti-cancer vaccine. The study highlights the importance of FAO in T_M-cell development and suggests that pharmacological modulation of T-cell metabolism could enhance vaccine efficacy.