SRP344395 PRJNA777572 GSE187456 Pantothenate metabolism fuels T cell antitumor immunity Metabolic programming is a central regulator of T cell activation, differentiation and effector function. These metabolic processes are intricately linked to the anti-tumor properties of T cells and manipulation of T cell metabolism has shown promise in enhancing immunotherapy. To gain further insight into the metabolic pathways associated with increased anti-tumor T cell function, we utilized a metabolomics approach to interrogate the metabolic profile of three different CD8+ T cell subsets each with varying degrees of anti-tumor activity in murine models. These subsets include IFN-?+ Tc1, IL-17+ Tc17 and IL-22+ Tc22 CD8+ effector subsets, of which Tc22 cells display the most robust anti-tumor activity. Here, we show that Tc22s were distinct in their up-regulation of the pantothenate/coenzyme A (CoA) pathway and requirement for oxidative phosphorylation (OXPHOS) for differentiation. Further investigation revealed that the exogenous administration of CoA metabolically reprogrammed T cells to increase OXPHOS and adopt the CD8+ Tc22 phenotype independent of polarizing conditions via the transcription factors HIF-1a and the aryl hydrocarbon receptor (AhR). CoA-treated CD8+ T cells demonstrated enhanced anti-tumor function and persistence following adoptive transfer in murine tumor models. Treatment of mice with the CoA precursor pantothenate also enhanced the efficacy of anti-PD-L1 antibody therapy in preclinical models. These findings were extended to human melanoma patients, as we correlated increased pre-treatment plasma pantothenate levels with response to anti-PD1 antibody therapy. Collectively, our data demonstrate that pantothenate and its metabolite CoA drive T cell polarization, bioenergetics and anti-tumor immunity. Overall design: Tc0 cells, Tc22 cells and Tc0 cells treated with CoA, compared in triplicate. All cell populations were extracted from each mouse (matched per sample). GSE187456