The proliferation and differentiation of anti-tumor T cells is regulated by antigen and cytokine signals but the induction of metabolic pathways is also required, resulting in an integration of environmental cues in cell fate decisions. While the mechanisms governing an optimal anti-tumor T cell response remain largely undefined, long-term anti-tumor T cell function may be optimized by promoting a bioenergetics profile that minimizes terminal memory differentiation and exhaustion. Indeed, T lymphocyte activation is regulated by the metabolism of different nutrients, allowing the cell to meet increased energetic and biosynthetic demands. Notably, we recently found that glutamine availability is a key determinant of T cell differentiation; CD4 lymphocytes undergo differentiation to IFNg-secreting Th1 effectors under conditions of optimal glutaminolysis but are converted to Forkhead box P3 (Foxp3)⁺ regulatory T cells when glutamine catabolism is abrogated. We now show that the glutamine-derived metabolite, a-ketoglutarate (aKG) increases oxidative phosphorylation (OXPHOS) in naïve CD4 T cells activated under Treg polarizing condition, significantly augmenting IFNg-secretion while attenuating Foxp3⁺ cell generation. Under these conditions, adoptive transfer of aKG-treated chimeric antigen receptor (CAR)-engineered T cells against the ErbB2 tumor antigen in tumor-bearing mice, results in enhanced tumor infiltration and decreased Foxp3 expression. Mechanistically, we found that aKG-induced OXPHOS is associated with lipidome remodelling, characterized by augmented mitochondrial lipids and triacylglyceride (TAG) stores. Conversely, inhibiting DGAT2-mediated TAG synthesis significantly augments Treg polarization and decreases inflammatory cytokine secretion. Thus, our study identifies the potential of a single metabolite to translate metabolic signals into an enhanced anti-tumor CAR-T cell response.