Prostate cancer (PCa) is the second most common cancer in males. Androgen deprivation therapy (ADT) serves as the primary non-surgical treatment approach. However, the frequent progression to castration-resistant PCa after ADT drives the need for new therapeutic modalities in PCa. In recent years, tumor immunotherapy has made significant progress in the treatment of many tumors, but clinically, only a small number of PCa patients benefit from immunotherapy because of cold immune microenvironment. Many studies have shown that sialic acid metabolism is related to the immunosuppressive tumor microenvironment (TME). Utilizing RNA sequencing data in The Cancer Genome Atlas (TCGA), we investigated the association between sialic acid metabolism-related genes and the carcinogenesis of PCa. Based on both transcriptomic and proteomics data, we discovered that the high expression of the cathepsin A (CTSA) is associated with the tumorigenesis and poor prognosis of PCa. Further pathway enrichment analysis revealed that CTSA is related to several immunity-associated pathways. We validated the role of CTSA in the TME of PCa using single-cell RNA sequencing. Through animal experiments and fluorescence staining, we demonstrated that CTSA contributes to the formation of immunosuppressive TME. Targeting CTSA provides a potential effective for PCa treatment and enhances immunotherapy efficacy.

1. Rebello RJ, Oing C, Knudsen KE, et al. Prostate cancer. Nat Rev Dis Primers. 2021;7(1):9. doi: 10.1038/s41572-020-00243-0

2. Desai K, McManus JM, Sharifi N. Hormonal therapy for prostate cancer. Endocr Rev. 2021;42(3):354-373. doi: 10.1210/endrev/bnab002

3. Bergengren O, Pekala KR, Matsoukas K, et al. 2022 update on prostate cancer epidemiology and risk factors-a systematic review. Eur Urol. 2023;84(2):191-206. doi: 10.1016/j.eururo.2023.04.021

4. Beer TM, Kwon ED, Drake CG, et al. Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol. 2017;35(1):40-47. doi: 10.1200/jco.2016.69.1584

5. Powles T, Yuen KC, Gillessen S, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: A randomized phase 3 trial. Nat Med. 2022;28(1):144-153. doi: 10.1038/s41591-021-01600-6

6. McNevin CS, Keogh A, Mohammed Nur M, et al. Prevalence of mismatch repair deficiency in primary prostate cancer in a large prospective cohort. Clin Cancer Res. 2025;31(9):1746-1753. doi: 10.1158/1078-0432.Ccr-24-1210

7. Lenis AT, Ravichandran V, Brown S, et al. Microsatellite instability, tumor mutational burden, and response to immune checkpoint blockade in patients with prostate cancer. Clin Cancer Res. 2024;30(17):3894-3903. doi: 10.1158/1078-0432.Ccr-23-3403

8. Bilusic M, Madan RA, Gulley JL. Immunotherapy of prostate cancer: Facts and hopes. Clin Cancer Res. 2017;23(22):6764-6770. doi: 10.1158/1078-0432.Ccr-17-0019

9. Xie T, Fu DJ, Li ZM, et al. CircSMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR- 1322/CCL20/CCR6 signaling. Mol Cancer. 2022;21(1):173. doi: 10.1186/s12943-022-01630-9

10. Kiviaho A, Eerola SK, Kallio HML, et al. Single cell and spatial transcriptomics highlight the interaction of club-like cells with immunosuppressive myeloid cells in prostate cancer. Nat Commun. 2024;15(1):9949. doi: 10.1038/s41467-024-54364-1

11. Xu F, Wang X, Huang Y, et al. Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8(+) T cell. Cell Rep. 2023;42(11):113424. doi: 10.1016/j.celrep.2023.113424

12. Liu Z, Liu W, Wang W, et al. CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing. Proc Natl Acad Sci U S A. 2023;120(39):e2302878120. doi: 10.1073/pnas.2302878120

13. Büll C, Stoel MA, den Brok MH, Adema GJ. Sialic acids sweeten a tumor’s life. Cancer Res. 2014;74(12):3199-3204. doi: 10.1158/0008-5472.Can-14-0728

14. Stanczak MA, Rodrigues Mantuano N, Kirchhammer N, et al. Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade. Sci Transl Med. 2022;14(669):eabj1270. doi: 10.1126/scitranslmed.abj1270

15. Wen RM, Stark JC, Marti GEW, et al. Sialylated glycoproteins suppress immune cell killing by binding to Siglec-7 and Siglec-9 in prostate cancer. J Clin Invest. 2024;134(24):e180282. doi: 10.1172/jci180282

16. Cao K, Zhang G, Yang M, et al. Attenuation of sialylation augments antitumor immunity and improves response to immunotherapy in ovarian cancer. Cancer Res. 2023;83(13):2171-2186. doi: 10.1158/0008-5472.Can-22-3260

17. Ou W, Zhang XX, Li B, et al. Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies. Nat Commun. 2025;16(1):3189. doi: 10.1038/s41467-025-58569-w

18. Gorelik A, Illes K, Mazhab-Jafari MT, Nagar B. Structure of the immunoregulatory sialidase NEU1. Sci Adv. 2023;9(20):eadf8169. doi: 10.1126/sciadv.adf8169

19. Caciotti A, Catarzi S, Tonin R, et al. Galactosialidosis: Review and analysis of CTSA gene mutations. Orphanet J Rare Dis. 2013;8:114. doi: 10.1186/1750-1172-8-114

20. Gorelik A, Illes K, Hasan SMN, Nagar B, Mazhab-Jafari MT. Structure of the murine lysosomal multienzyme complex core. Sci Adv. 2021;7(20):eabf4155. doi: 10.1126/sciadv.abf4155

21. Ni S, Weng W, Xu M, et al. miR-106b-5p inhibits the invasion and metastasis of colorectal cancer by targeting CTSA. Onco Targets Ther. 2018;11:3835-3845. doi: 10.2147/ott.S172887

22. Kozlowski L, Wojtukiewicz MZ, Ostrowska H. Cathepsin A activity in primary and metastatic human melanocytic tumors. Arch Dermatol Res. 2000;292(2-3):68-71. doi: 10.1007/s004030050012

23. Hu B, Zhu X, Lu J. Cathepsin A knockdown decreases the proliferation and invasion of A549 lung adenocarcinoma cells. Mol Med Rep. 2020;21(6):2553-2559. doi: 10.3892/mmr.2020.11068

24. Zhang M, Huang J, Wang Y, et al. Cathepsin a upregulation in glioma: A potential therapeutic target associated with immune infiltration. J Med Biochem. 2022;41(4):459-465. doi: 10.5937/jomb0-35677

25. Park S, Kwon W, Park JK, et al. Suppression of cathepsin a inhibits growth, migration, and invasion by inhibiting the p38 MAPK signaling pathway in prostate cancer. Arch Biochem Biophys. 2020;688:108407. doi: 10.1016/j.abb.2020.108407

26. Henry GH, Malewska A, Joseph DB, et al. A cellular anatomy of the normal adult human prostate and prostatic urethra. Cell Rep. 2018;25(12):3530-3542.e5. doi: 10.1016/j.celrep.2018.11.086

27. Wang Z, Zhang X, Li W, et al. ATM/NEMO signaling modulates the expression of PD-L1 following docetaxel chemotherapy in prostate cancer. J Immunother Cancer. 2021;9(7):e001758. doi: 10.1136/jitc-2020-001758

28. Liu R, Un H, Lin R, et al. Single-cell and bulk RNA-sequence identify an immune-derived lncRNA-mRNA signature for predicting clinical outcomes and immunotherapeutic response of prostate cancer. Int J Biol Macromol. 2025;309(Pt 3):143014. doi: 10.1016/j.ijbiomac.2025.143014

29. Toss MS, Miligy IM, Haj-Ahmad R, et al. The prognostic significance of lysosomal protective protein (cathepsin A) in breast ductal carcinoma in situ. Histopathology. 2019;74(7):1025-1035. doi: 10.1111/his.13835

30. Wang H, Xu F, Yang F, Lv L, Jiang Y. Prognostic significance and oncogene function of cathepsin A in hepatocellular carcinoma. Sci Rep. 2021;11(1):14611. doi: 10.1038/s41598-021-93998-9

31. Koinis F, Xagara A, Chantzara E, Leontopoulou V, Aidarinis C, Kotsakis A. Myeloid-derived suppressor cells in prostate cancer: Present knowledge and future perspectives. Cells. 2021;11(1):20. doi: 10.3390/cells11010020

32. Calcinotto A, Spataro C, Zagato E, et al. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature. 2018;559(7714):363-369. doi: 10.1038/s41586-018-0266-0

33. Yokokawa J, Cereda V, Remondo C, et al. Enhanced functionality of CD4+CD25(high)FoxP3+ regulatory T cells in the peripheral blood of patients with prostate cancer. Clin Cancer Res. 2008;14(4):1032-1040. doi: 10.1158/1078-0432.Ccr-07-2056

34. Li C, Xu X, Wei S, Jiang P, Xue L, Wang J. Tumor-associated macrophages: Potential therapeutic strategies and future prospects in cancer. J Immunother Cancer. 2021;9(1):e001341. doi: 10.1136/jitc-2020-001341

35. Lanciotti M, Masieri L, Raspollini MR, et al. The role of M1 and M2 macrophages in prostate cancer in relation to extracapsular tumor extension and biochemical recurrence after radical prostatectomy. Biomed Res Int. 2014;2014:486798. doi: 10.1155/2014/486798

36. Erlandsson A, Carlsson J, Lundholm M, et al. M2 macrophages and regulatory T cells in lethal prostate cancer. Prostate. 2019;79(4):363-369. doi: 10.1002/pros.23742

37. Shu X, Li J, Chan UI, et al. BRCA1 insufficiency induces a hypersialylated acidic tumor microenvironment that promotes metastasis and immunotherapy resistance. Cancer Res. 2023;83(15):2614-2633. doi: 10.1158/0008-5472.Can-22-3398

38. Goode EA, Orozco-Moreno M, Hodgson K, et al. Sialylation inhibition can partially revert acquired resistance to enzalutamide in prostate cancer cells. Cancers (Basel). 2024;16(17):2953. doi: 10.3390/cancers16172953

39. Hodgson K, Orozco-Moreno M, Goode EA, et al. Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone. EBioMedicine. 2024;104:105163. doi: 10.1016/j.ebiom.2024.105163

40. Munkley J. Aberrant sialylation in cancer: Therapeutic opportunities. Cancers (Basel). 2022;14(17):4248. doi: 10.3390/cancers14174248

41. Duarte HO, Rodrigues JG, Gomes C, et al. ST6Gal1 targets the ectodomain of ErbB2 in a site-specific manner and regulates gastric cancer cell sensitivity to trastuzumab. Oncogene. 2021;40(21):3719-3733. doi: 10.1038/s41388-021-01801-w

42. Smithson M, Irwin R, Williams G, et al. Sialyltransferase ST6GAL-1 mediates resistance to chemoradiation in rectal cancer. J Biol Chem. 2022;298(3):101594. doi: 10.1016/j.jbc.2022.101594

43. Chakraborty A, Dorsett KA, Trummell HQ, et al. ST6Gal-I sialyltransferase promotes chemoresistance in pancreatic ductal adenocarcinoma by abrogating gemcitabine-mediated DNA damage. J Biol Chem. 2018;293(3):984-994. doi: 10.1074/jbc.M117.808584

44. Tuong ZK, Loudon KW, Berry B, et al. Resolving the immune landscape of human prostate at a single-cell level in health and cancer. Cell Rep. 2021;37(12):110132. doi: 10.1016/j.celrep.2021.110132