Adoptive T cell therapy (ACT) has been established as an efficacious methodology for the treatment of cancer. Identifying targets to enhance the antigen recognition, functional capacity, and longevity of T cells has the potential to broaden the applicability of these approaches in the clinic. We previously reported that targeting expression of phosphotyrosine phosphatase, nonreceptor type 22 (PTPN22) in effector CD8+ T cells enhances the efficacy of ACT for tumor clearance in mice. In the current work, we demonstrate that, upon ACT, PTPN22-deficient effector CD8+ T cells afforded greater protection against tumors expressing very low-affinity antigen but did not survive long term in vivo. Persistence of CD8+ T cells following tumor clearance was improved by ACT of memory phenotype cells that have a distinct metabolic phenotype, as compared with effector T cells. Importantly, PTPN22-deficient T cells have comparable capacity to form long-lived memory cells in vivo but enhanced antitumor activity in vivo and effector responses ex vivo. These findings provide key insights into the regulation of effector and memory T cell responses in vivo and indicate that PTPN22 is a rational target to improve ACT for cancer.