Journal of Peking University (Health Sciences) ›› 2026, Vol. 58 ›› Issue (4): 770-778. doi: 10.19723/j.issn.1671-167X.2026.04.013

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A multi-level study of androgen deprivation therapy on the immune microenvironment in prostate cancer

Zhongyu TAN, Yiqing DU, Caipeng QIN*(), Tao XU*()   

  1. Department of Urology, Peking University People' s Hospital, Beijing 100044, China
  • Received:2026-03-02 Online:2026-08-18 Published:2026-05-27
  • Contact: Caipeng QIN, Tao XU
  • Supported by:
    the National Natural Science Foundation of China(82371840); the Beijing Natural Science Foundation(7262134)

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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

CLC Number: 

  • R737.25

Table 1

Clinical information of the patients undergoing ADT treatment"

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

Figure 1

Trends of serum PSA and androgen changes in prostate cancer patients undergoing ADT treatment The dynamic changes of serum PSA (A), serum free testosterone (B), and serum testosterone (C) in 12 patients undergoing ADT treatment over a one-year period. PSA, prostate specific antigen; ADT, androgen deprivation therapy."

Figure 2

Dynamic changes of peripheral blood immune cells and immune-related factors in prostate cancer patients undergoing ADT treatment Flow cytometry was used to detect the changes in the proportion of peripheral blood immune cells in patients before and after ADT treatment (A), and antibody arrays were used to detect the changes in immune-related factors (B). IL, interleukin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; TNF, tumor necrosis factor; PDGF, platelet derived growth factor; BLC, B lymphocyte chemoattractant; RANTES, regulated on activation normal T cell expressed and secreted; MIP, major intrinsic protein of lens fiber; MCP, membrane cofactor protein; G-CSF, granulocyte colony-stimulating factor; TIMP, tissue inhibitor of metalloproteinases; MCSF, macrophage colony-stimulating factor, ICAM, intercellular adhesion molecule; MIG, monokine induced by interferon-γ."

Figure 3

Transcriptomic analysis of the effects of castration on gene expression and tumor microenvironment in prostate cancer PDX tissues RNAseq data from five prostate cancer PDX models of GEO (GSE41193) were analyzed before and after surgical castration. Differential genes were displayed, with A being a volcano plot, B being a MA plot, C being a Top200 differential gene heatmap, and D being a GO analysis. ssGSEA was applied to analyze the expression ratios of various immune cells before and after surgical castration, and Wilcoxon rank-sum test was used for inter-group difference comparison, with *P < 0.05, * *P < 0.01, * * *P < 0.001 (E). GSVA was also applied to perform enrichment analysis on immune-related pathways, with NES >1 and FDR < 0.05 as the significant criteria for pathway enrichment (F). FC, fold change; PDX, patient-derived tumor xenograft; GEO, gene expression omnibus; MA, mean-difference; GO, gene expression omnibus; ssGSEA, single-sample gene set enrichment analysis; GSVA, gene set variation analysis; NES, normalized enrichment score; FDR, false discovery rate."

Figure 4

Initial cell clustering of scRNAseq data from four prostate cancer tissues (two cases received ADT treatment) Using marker genes, single cells were initially grouped into three major populations: immune cells, stromal cells, and epithelial cells, which were then visualized using tSNE (A) and UMAP (B). Subsequently, subpopulation analysis was performed on these three major populations, resulting in the identification of eight subpopulations (C). The distribution of each subpopulation in each case was statistically presented (D). tSNE, t-distributed stochastic neighbor embedding; UMAP, uniform manifold approximation and projection."

Figure 5

Annotation of T-cell subpopulations in prostate cancer Through clustering analysis of T cells, a total of 14 T cell subpopulations were obtained (A). T cell subpopulation markers were used to annotate the subpopulations (B, C), with a focus on the expression of CD4+T cells and CD8+T cells in different groups (D)."

Figure 6

Effect of ADT treatment on T cell function After ADT treatment, the expression of genes related to T cells and cytotoxicity was downregulated (A). Specifically, the expression of NKG7, GZMB, and GZMA in CD8+T cells was significantly downregulated, and the expression of genes related to T regulatory cell function, such as CCL4, LGALS3, and LAG3, also showed a downward trend. GSVA enrichment analysis was performed on the differential genes of CD4+T cells and CD8+T cells in the Hallmark 50 gene pathways. ADT treatment led to the downregulation of the interferon pathway (C). ADT, androgen deprivation therapy; FC, fold change; GSVA, gene set variation analysis."

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