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Background The efficacy of CAR-T cells against solid tumors is limited by the suppressive tumor microenvironment and T cell exhaustion. Although numerous T cell engineering approaches have attempted to enhance CAR-T activity, few have effectively altered T cells so that they are epigenetically and transcriptionally reprogrammed away from an exhausted state and towards a potent therapeutic state. Here, we investigate the function and biology of a synthetic gene, called a Synthetic Pathway Activator (SPA), that is modeled on natural cytokine receptors and designed to overcome these challenges.Methods We discovered the SPA via a large-scale screening campaign with a library of synthetic cytokine receptors to identify those that increase the potency, expansion and persistence of autologous T cells. The top performing candidates were tested using in vitro functional assays measuring CAR-T potency and in vivo xenograft methods. To gain a molecular understanding of how SPA modulates CAR-T cells, we conducted a 14 day Repetitive Stimulation Assay (RSA) with tumor antigen expressing target cells, designed to recapitulate the conditions that drive exhaustion, coupled with single cell RNAseq (scRNAseq) and ATACseq, to map the transcriptional trajectory of CAR-T cells.Results Candidate SPA designs conferred an increase in STAT1 and STAT3 activity as well as heightened granzyme B and IL-10 levels. SPA-expressing CAR-T cells increased cytotoxicity and expansion in vitro, and did not confer cytokine-independent growth or extended survival. In xenograft models, SPA-enhanced CAR-T cells outperformed unmodified CAR-T cells in controlling tumor volume with a 25-fold gain in potency. The long term RSA functional readout confirmed that SPA encoding CAR-T cells outperform non-SPA cells in controlling tumor outgrowth. Molecular readouts revealed that the SPA confers a distinct differentiation trajectory compared to controls. Control CAR-T cells developed hallmark features of exhaustion including expression of TOX, a master transcriptional regulator of exhaustion in T cells, and chromatin accessibility at enhancers for exhaustion-related genes. In contrast, SPA cells maintained expression of memory markers, showed altered co-inhibitory molecule expression, and failed to induce TOX. ATAC-seq analysis showed that SPA cells did not remodel chromatin at the TOX enhancer locus, suggesting an altered transcriptional program as the mechanism of failed TOX induction.Conclusions Expression of the SPA increases CAR-T effector function while simultaneously reprogramming T cells away from exhaustion. The SPA therefore induces a unique T cell-intrinsic genetic program with the potential to overcome a key limitation of cell therapies targeting solid tumors.