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Although the intracellular antioxidant paraoxonase 2 (PON2) is frequently dysregulated across multiple cancers, its biological role in ccRCC\u2014particularly the contribution of its enzymatic activity and interplay with the tumor immune microenvironment\u2014remains poorly defined. Methods: Multi-cohort analysis integrating TCGA, ICGC, GEO, and CPTAC datasets was combined with single-cell transcriptomic profiling, survival and Cox regression modeling, immune infiltration estimation, and in vitro loss- and gain-of-function experiments in ccRCC cell lines. Results: PON2 was markedly elevated in ccRCC tissues, predominantly localizing to malignant epithelial and endothelial cells as determined by single-cell transcriptomic profiling. High PON2 expression correlated with advanced T\/M stages and independently predicted poor prognosis. Functional experiments showed that PON2 silencing was associated with reduced tumor cell proliferation, invasion, and glycolysis, while rescue experiments using wild-type\u2014but not S311C mutant\u2014PON2 partially restored these phenotypes. PON2 expression was associated with glycolysis-related metabolic changes and CEBPB-related expression of downstream glycolytic targets, including LDHA and PGK1. Furthermore, PON2-high tumors showed transcriptomic features consistent with an immunosuppressive microenvironment, with higher computational estimates of CD8+ T-cell infiltration accompanied by elevated immune checkpoint expression (PD-L1, CTLA4) and higher estimated abundance of immunosuppressive populations (Tregs, MDSCs). Conclusions: Collectively, our findings identify PON2 as a candidate biomarker associated with ccRCC progression and CEBPB-related glycolysis and features consistent with an immunosuppressive microenvironment.<\/jats:p>","DOI":"10.3390\/cancers18193086","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T08:14:39Z","timestamp":1790151279000},"page":"3086","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of PON2 and Its S311C Substitution with Tumor Progression and Its Significance as an Immune-Associated Prognostic Indicator in Clear Cell Renal Cell Carcinoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Zhiyu","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Wei","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Ting","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"given":"Chuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Guangming","family":"He","sequence":"additional","affiliation":[{"name":"Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Shenglin","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2975-2658","authenticated-orcid":false,"given":"Xiaokai","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"given":"Li","family":"Zuo","sequence":"additional","affiliation":[{"name":"Department of Urology & Urology Laboratory, The Third Affiliated Hospital of Nanjing Medical University, 68 Gehu Middle Road, Wujin District, Changzhou 213003, 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