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Background Radiopharmaceutical therapy (RPT) delivers radiation systemically, enabling the treatment of metastatic cancers. Beyond killing tumor cells, RPT can modulate the tumor immune microenvironment. With RPTs and immunotherapies already approved or in development for prostate cancer, many preclinical and clinical studies are evaluating their use in combination. However, due to the radiosensitivity of tumor-infiltrating lymphocytes, further studies are needed to determine the effects of RPT on these cells to better inform the sequence of immunotherapies that activate T cells when given with RPT.Methods E.G7-OVA tumor-bearing mice received naïve or activated OT-I CD8+T cells prior to or following the administration of RPT using 90Y-NM600. Changes in tumor growth were monitored, and tumor-infiltrating lymphocytes were evaluated for phenotypic and functional markers. The murine prostate tumor model TRAMP-C1 was used to evaluate this approach using tumor antigen-specific vaccination with 90Y-NM600.Results Antitumor efficacy was improved if OT-I CD8+T cells were present and activated prior to 90Y-NM600 administration than if the cells were delivered after RPT. Similarly, in vivo activation of adoptively transferred OT-I CD8+T cells, using ovalbumin (OVA)-specific vaccination, prior to RPT slowed tumor growth and increased the frequency of tumor-infiltrating OVA257-264-specific CD8+T cells with effector memory phenotype and effector molecule production. Blockade of type I interferon, but not the upstream inhibition of stimulator of interferon genes, abrogated tumor growth delay resulting from the combination treatment. Tumor antigen-specific vaccination prior to 90Y-NM600 administration similarly improved antitumor outcomes in the TRAMP-C1 tumor model.Conclusions Our study suggests that tumor-specific CD8+T cells need to be present and activated prior to RPT to enhance antitumor outcomes. This study highlights the importance of considering the effects of RPT on tumor-infiltrating CD8+T cells when combining other T-cell activating therapies with RPT, as they may similarly display sequence-dependent antitumor outcomes.