雄激素剥夺治疗对前列腺癌免疫微环境影响的多层级研究

doi:10.19723/j.issn.1671-167X.2026.04.013

摘要/Abstract

摘要：

目的: 从免疫水平、动物模型转录组及单细胞组学层面系统评估雄激素剥夺治疗(androgen deprivation therapy，ADT)对前列腺癌免疫微环境的影响，阐明ADT介导的肿瘤免疫重塑特征。方法: 纳入北京大学人民医院接受ADT治疗的前列腺癌患者12例，动态检测血清前列腺特异性抗原(prostate specific antigen，PSA)、睾酮水平、外周血免疫细胞比例与细胞因子表达变化；从基因表达汇编(gene expression omnibus，GEO)数据库下载前列腺癌人源肿瘤异种移植(patient-derived tumor xenograft，PDX)模型去势前后转录组数据(GSE41193，共5例)，进行相关生物信息学分析；另对4例前列腺癌组织(2例接受ADT新辅助治疗、2例未接受)行单细胞RNA测序(single-cell RNA sequencing，scRNA-seq)，解析肿瘤微环境细胞组成及T细胞功能状态。结果: ADT显著降低患者血清PSA及睾酮水平，但外周血免疫细胞比例及大多数细胞因子无明显影响。PDX模型分析显示, 前列腺癌患者去势后差异表达基因富集于神经相关及免疫调控通路，多种免疫细胞浸润特征呈现趋势性改变。scRNA-seq结果表明, ADT治疗后肿瘤内效应性CD8⁺T细胞比例下降，GZMA、GZMB、GNLY、NKG7等细胞毒相关基因表达下调，而调节性T细胞(Treg)相对富集。Hallmark通路分析显示干扰素信号通路受到抑制。结论: ADT可诱导前列腺癌肿瘤免疫微环境发生趋势性的改变，表现为T细胞杀伤功能减弱及免疫抑制性细胞富集，提示ADT可能促进抑制性肿瘤免疫微环境(tumor immune microenvironment，TIME)形成，为ADT联合免疫调节治疗策略提供了理论依据。

关键词: 前列腺癌, 雄激素剥夺治疗, 肿瘤免疫微环境

Abstract:

Objective: To systematically evaluate the impact of androgen deprivation therapy (ADT) on the immune microenvironment of prostate cancer at the levels of systemic immunity, animal model transcriptomics, and single-cell omics, and to elucidate the characteristics of ADT-mediated tumor immune remodeling. Methods: Twelve prostate cancer patients who received ADT at Peking University People' s Hospital were enrolled. Dynamic monitoring of serum prostate specific antigen (PSA), testosterone levels, peripheral blood immune cell proportions, and cytokine expression changes was performed. Transcriptomic data from patient-derived tumor xenograft (PDX) models before and after castration (GSE41193, 5 cases in total) were downloaded from the gene expression omnibus (GEO) database for relevant bioinformatics analyses. Single-cell RNA sequencing (scRNA-seq) was performed on 4 prostate cancer tissue samples (2 received neoadjuvant ADT, 2 untreated) to analyze tumor microenvironment cell composition and T-cell functional states. Results: ADT significantly reduced serum PSA and testosterone levels in the patients, but had no significant effect on peripheral blood immune cell proportions or most cytokines. PDX model analysis showed that differentially expressed genes after castration were enriched in neural-related and immune regulation pathways, with trending changes observed in the infiltration characteristics of various immune cells. scRNA-seq results indicated a decreased proportion of intratumoral effector CD8⁺ T cells after ADT treatment, with downregulated expression of cytotoxicity-related genes, such as GZMA, GZMB, GNLY, and NKG7, while regulatory T cells (Tregs) were relatively enriched. Hallmark pathway analysis revealed suppression of interferon signaling pathways. Conclusion: The preliminary results of this study suggest that ADT can induce a trend of change in the tumor immune microenvironment of prostate cancer, characterized by weakened T-cell killing function and enrichment of immunosuppressive cells. This suggests that ADT may promote the formation of an immunosuppressive tumor immune microenvironment (TIME), providing a theoretical basis for ADT combined with immune-modulating therapeutic strategies.

Key words: Prostate cancer, Androgen deprivation therapy, Tumor immune microenvironment

中图分类号:

R737.25

谭仲宇, 杜依青, 秦彩朋, 徐涛. 雄激素剥夺治疗对前列腺癌免疫微环境影响的多层级研究[J]. 北京大学学报（医学版）, 2026, 58(4): 770-778.

Zhongyu TAN, Yiqing DU, Caipeng QIN, Tao XU. A multi-level study of androgen deprivation therapy on the immune microenvironment in prostate cancer[J]. Journal of Peking University (Health Sciences), 2026, 58(4): 770-778.

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参考文献 14

1	Li M , Bai G , Cen Y , et al. Silencing HOXC13 exerts anti-prostate cancer effects by inducing DNA damage and activating cGAS/STING/IRF3 pathway[J]. J Transl Med, 2023, 21(1): 884. doi: 10.1186/s12967-023-04743-x
2	Kumar A , Reddy A , Sekar A . Enzalutamide induced non-ischemic cardiomyopathy. A case report and review of literature on anti-androgen therapy-related cardiovascular events[J]. Cardio Oncol, 2023, 9(1): 9. doi: 10.1186/s40959-023-00160-7
3	Liu Y , Shi Y , Cao Y , et al. Development of a metabolism-associated prognostic risk model based on immune landscape stratification in prostate cancer[J]. Discov Oncol, 2025, 16(1): 1733. doi: 10.1007/s12672-025-03269-6
4	Zhao D , Mo Z , Zhang T , et al. Lactate derived from cancer-associated fibroblasts promotes alternative splicing and castration resistance in prostate cancer[J]. Sci Adv, 2026, 12(3): eady5324. doi: 10.1126/sciadv.ady5324
5	Liu L , Rascón IA , Lin D , et al. CXCR4-LASP1-G9a-SNAIL axis drives NEPC transdifferentiation via induction of EMT and downregulation of REST[J]. Cell Genom, 2025, 5(8): 100916. doi: 10.1016/j.xgen.2025.100916
6	Dallos MC , Obradovic AZ , McCann P , et al. Androgen deprivation therapy drives a distinct immune phenotype in localized prostate cancer[J]. Clin Cancer Res, 2024, 30(22): 5218- 5230. doi: 10.1158/1078-0432.CCR-24-0060
7	Cobos FA , Panah MJN , Epps J , et al. Effective methods for bulk RNA-seq deconvolution using scnRNA-seq transcriptomes[J]. Genome Biol, 2023, 24(1): 177. doi: 10.1186/s13059-023-03016-6
8	Wang H , Huang H , Liu T , et al. Peripheral blood lymphocyte subsets predict the efficacy of TACE with or without PD-1 inhibitors in patients with hepatocellular carcinoma: A prospective clinical study[J]. Front Immunol, 2024, 15, 1325330. doi: 10.3389/fimmu.2024.1325330
9	Venkadakrishnan VB , Presser AG , Singh R , et al. Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes[J]. Nat Commun, 2024, 15, 6779. doi: 10.1038/s41467-024-51156-5
10	Guan X , Polesso F , Wang C , et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy[J]. Nature, 2022, 606(7915): 791- 796. doi: 10.1038/s41586-022-04522-6
11	Izumi K , Mizokami A . Suppressive role of androgen/androgen receptor signaling via chemokines on prostate cancer cells[J]. J Clin Med, 2019, 8(3): 354. doi: 10.3390/jcm8030354
12	Wen R , Huang X , Long J , et al. Advances in traditional Chinese herbal medicine and their pharmacodynamic mechanisms in cancer immunoregulation: A narrative review[J]. Transl Cancer Res, 2024, 13(2): 1166- 1187. doi: 10.21037/tcr-23-1983
13	Lin Y , Jin H , She Y , et al. CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex[J]. Proc Natl Acad Sci USA, 2025, 122(5): e2417529122. doi: 10.1073/pnas.2417529122
14	Klawon DEJ , Pagane N , Walker MT , et al. Regulatory T cells constrain T cells of shared specificity to enforce tolerance during infection[J]. Science, 2025, 387(6740): eadk3248. doi: 10.1126/science.adk3248

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Case	Age/years	Baseline PSA/(μg/L)	f/t PSA	Gleason score	Clinical stage
1	79	23.21	0.09	3+4	T4N0M0
2	84	25.64	0.09	4+3	T2N0M0
3	77	68.44	0.05	4+5	T3bN0M0
4	81	18.63	0.07	3+4	T1cN0M0
5	81	9.06	0.14	3+4	T2N0M0
6	77	13.61	0.23	3+3	T1cN0M0
7	64	65.84	0.07	4+3	T2N0M1b
8	80	76.27	0.2	3+4	T2N0M1b
9	64	172.70	0.08	4+3	T4N1M1b
10	83	18.17	0.24	3+3	T2N0M0
11	83	17.86	0.11	4+4	T4N0M0
12	85	15.08	0.08	4+3	T4N0M0