Comprehensive metastasis-directed therapy (MDT) for oligometastatic prostate cancer extended progression-free survival (PFS) and time to new lesion formation in the intermittent hormone therapy (HT) basket of EXTEND. To better understand the mechanism of MDT benefit, we pooled the intermittent and continuous HT baskets of EXTEND and tested the hypothesis that adding MDT to HT would program systemic T-cells to control micrometastatic disease. A total of 174 men were randomized to HT with or without MDT to up to 5 sites of metastases. HT was given for 6 months (intermittent basket, n = 87) or indefinitely (continuous basket, n = 87). Peripheral blood samples were drawn at enrollment, at the end of MDT, at 3 months follow-up (3 mo F/U), and at progression and then analyzed by flow cytometry, T-cell receptor (TCR)-β CDR3 variable region sequencing, multiplex cytokine profiling, and next-generation circulating tumor DNA (ctDNA) sequencing. TCR clonal expansion was determined using a published betabinomial model. Repertoire changes were assessed by Morisita's index, and dominant TCR repertoire motifs were characterized with ImmunoMap. Associations between blood markers and PFS were evaluated with Cox regression adjusted hazard ratios (aHR) accounting for randomization arm and stratifying for intermittent vs continuous HT. Randomization to MDT+HT was associated with T-cell activation, proliferation, and clonal expansion. This response was first observed at end-MDT as upregulated expression of T-cell activation and inhibition markers (i.e., ICOS, Tim-3, and LAG-3) and increases in highly proliferative CD4+ and CD8+ Ki67hi T-cells (all P<0.05). TCR sequencing of 7,678,911 T-cells revealed that MDT+HT was associated with TCR clonal expansion, remodeling of the TCR repertoire, and changes in dominant TCR motifs at end-MDT and 3 mo F/U (all P<0.05). Observed T-cell priming could be driven by signaling networks of canonical T-cell stimulatory cytokines (IL-2, IL-12, and IL-15), which were upregulated at end-MDT and persisted at 3 mo F/U (all P<0.05). This modulation of T-cell phenotype, clonotype, and cytokine concentrations was not observed in the HT-monotherapy arm. At end-MDT, systemic T-cell responses were associated with improved PFS, most notably CD8+ T-cell expression of LAG-3 (aHR 0.22, 95% CI 0.03-0.91) and high TCR clonal expansion (aHR 0.13, 95% CI 0.02-0.52). High ctDNA burden at end-MDT correlated with worse PFS (aHR 1.41, 95% CI 1.04-2.54), as did CD8+ T-cell expression of inhibitory receptor TIGIT at 3 mo F/U (aHR 1.03, 95% CI 1.01-1.06). The addition of MDT to HT induced systemic T-cell activation and expansion, which was not observed in the HT-only arm. This systemic immune response was independently associated with improved PFS. In addition to cytoreduction of macroscopic disease, MDT-induced immune education may be an important complementary mechanism of micrometastatic control in oligometastatic prostate cancer.