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.

Background

Clear cell renal cell carcinoma (ccRCC), the predominant histological subtype of kidney malignancies, is characterized by metabolic dysregulation and therapeutic resistance. Although the intracellular antioxidant paraoxonase 2 (PON2) is frequently dysregulated across multiple cancers, its biological role in ccRCC-particularly the contribution of its enzymatic activity and interplay with the tumor immune microenvironment-remains 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-but not S311C mutant-PON2 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.