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When compared to other malignancies, the tumor microenvironment (TME) of primary and castration-resistant prostate cancer (CRPC) is relatively devoid of immune infiltrates. While androgen deprivation therapy (ADT) induces a complex immune infiltrate in localized prostate cancer, the composition of the TME in metastatic castration-sensitive prostate cancer (mCSPC), and the effects of ADT and other treatments in this context are poorly understood. Here, we perform a comprehensive single-cell RNA sequencing (scRNA-seq) profiling of metastatic sites from patients participating in a phase 2 clinical trial (NCT03951831) that evaluated standard-of-care chemo-hormonal therapy combined with anti-PD-1 immunotherapy. We perform a longitudinal, protein activity-based analysis of TME subpopulations, revealing immune subpopulations conserved across multiple metastatic sites. We also observe dynamic changes in these immune subpopulations in response to treatment and a correlation with clinical outcomes. Our study uncovers a therapy-resistant, transcriptionally distinct tumor subpopulation that expands in cell number in treatment-refractory patients. [Display omitted] • Protein-inferred activity clustering shows complex immune cells in CSPC metastases • ADT and aPD-1 treatment induces robust infiltrates of CD8+, CD4+ T cells, and Tregs • T cell infiltration determined by scRNA-seq correlated with T cells shown by qmIF • Baseline tumor and immune clusters associated with clinical outcomes TME composition of metastatic castration-sensitive prostate cancer (mCSPC) remains elusive. Hawley et al. perform scRNA-seq analysis of metastatic sites from mCSPC patients with ADT and anti-PD-1 treatment, identify tumor and immune subpopulations conserved across multiple metastatic sites, and reveal treatment-induced dynamic changes in these subpopulations and their correlation with clinical outcomes. [ABSTRACT FROM AUTHOR]