与其他恶性肿瘤相比，原发性前列腺癌和去势抵抗性前列腺癌（CRPC）的肿瘤微环境（TME）相对缺乏免疫浸润。虽然雄激素剥夺疗法 (ADT) 在局限性前列腺癌中诱导复杂的免疫浸润，但对转移性去势敏感型前列腺癌 (mCSPC) 中 TME 的组成以及 ADT 和其他治疗在这种情况下的作用知之甚少。在这里，我们对参与 2 期临床试验 (NCT03951831) 的患者的转移部位进行了全面的单细胞 RNA 测序 (scRNA-seq) 分析，该试验评估了标准护理化疗激素疗法与抗 PD-1 相结合的效果免疫疗法。我们对 TME 亚群进行了基于蛋白质活性的纵向分析，揭示了跨多个转移部位保守的免疫亚群。我们还观察了这些免疫亚群响应治疗的动态变化以及与临床结果的相关性。我们的研究发现了一种具有治疗抵抗性、转录上独特的肿瘤亚群，其在难治性患者中的细胞数量会增加。版权所有 © 2023。由 Elsevier Inc. 出版。

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.Copyright © 2023. Published by Elsevier Inc.