Wu Zhechun, Li Sihan, Li Yuqing, Wang Zhizhi, Wang Wei
Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
Institute of Urology, Capital Medical University, Beijing, China.
Discov Oncol. 2025 Sep 15;16(1):1428. doi: 10.1007/s12672-025-02985-3.
Prostate cancer (PCa) is a leading malignancy with a rising global incidence, posing significant challenges in treatment. The immunosuppressive tumor microenvironment (TME) in castration-resistant prostate cancer (CRPC) is a major barrier to effective immunotherapy. Identifying therapeutic targets that modulate the immune response within TME is crucial for advancing PCa treatment.
In this study, we employed Mendelian randomization (MR) to investigate the causal relationships between gene expression of blood proteins and PCa risk. We utilized cis-eQTL data from the eQTLGen Consortium and immune cell phenotype data from the NHGRI-EBI GWAS Catalog. Our analysis included primary and secondary cohorts, totaling over 800,000 individuals. Colocalization analysis was performed to confirm the genetic associations, and mediation MR analysis was used to explore the mediating role of proteins in tumor immunity. Drug prediction and molecular docking were applied to assess the potential of identified targets as druggable candidates.
Our MR analysis identified 557 proteins associated with PCa in the primary cohort, with 85 proteins remaining significant in another independent cohort. Mediation analysis revealed nine proteins that mediated the impact of immune cells on PCa. Colocalization analysis confirmed the causality of five proteins, which were further supported by phenome-wide association studies (PheWAS) and protein-protein interaction (PPI) networks. Molecular docking demonstrated strong binding affinity of potential drugs to these targets.
This study identified five drug targets in prostate cancer that modulate the tumor immune response. These targets may expedite drug development and personalize medicine, potentially enhancing treatment efficacy and reducing side effects.
前列腺癌（PCa）是一种主要的恶性肿瘤，全球发病率呈上升趋势，在治疗方面带来了重大挑战。去势抵抗性前列腺癌（CRPC）中的免疫抑制肿瘤微环境（TME）是有效免疫治疗的主要障碍。确定调节TME内免疫反应的治疗靶点对于推进PCa治疗至关重要。
在本研究中，我们采用孟德尔随机化（MR）来研究血液蛋白质基因表达与PCa风险之间的因果关系。我们利用了来自eQTLGen联盟的顺式eQTL数据和来自NHGRI-EBI GWAS目录的免疫细胞表型数据。我们的分析包括主要队列和次要队列，总计超过80万个体。进行共定位分析以确认遗传关联，并使用中介MR分析来探索蛋白质在肿瘤免疫中的中介作用。应用药物预测和分子对接来评估已鉴定靶点作为可成药候选物的潜力。
我们的MR分析在主要队列中鉴定出557种与PCa相关的蛋白质，其中85种蛋白质在另一个独立队列中仍然显著。中介分析揭示了9种介导免疫细胞对PCa影响的蛋白质。共定位分析证实了5种蛋白质的因果关系，全表型关联研究（PheWAS）和蛋白质-蛋白质相互作用（PPI）网络进一步支持了这一点。分子对接表明潜在药物与这些靶点具有很强的结合亲和力。
本研究在前列腺癌中鉴定出5个调节肿瘤免疫反应的药物靶点。这些靶点可能加快药物开发并实现个性化医疗，有可能提高治疗效果并减少副作用。
