Molecular Remodeling of Peritumoral Tissue in Clear Cell Renal Cell Carcinoma: Insights into Inflammaging and Prognostic Markers

Background/Objectives: Renal cell carcinoma (RCC) is a common and often asymptomatic malignancy with limited treatment options for advanced stages. Chronic inflammation and cellular senescence—collectively termed “inflammaging”—are emerging as key contributors to tumor progression. This study aimed to investigate the expression of inflammaging-related markers in RCC tissues, focusing on the role of PTX3, IL-6, and senescence-associated proteins in the tumor microenvironment. Methods: A retrospective cohort of 57 patients with clear cell RCC who underwent nephrectomy was analyzed. Formalin-fixed paraffin-embedded samples from tumor, peritumoral, and normal renal tissues were examined using confocal immunofluorescence microscopy to assess PTX3, IL-6, p21, and p16 expression. Senescence-associated β-galactosidase staining was performed to identify senescent cells. Serum IL-6 levels were measured by ELISA, and survival analysis was conducted using Kaplan–Meier curves and Cox regression analysis. Results: PTX3 and IL-6 were significantly upregulated in both peritumoral and tumor tissues compared to normal kidney samples (p < 0.001). Expression of senescence markers p21 and p16 were elevated in peritumoral areas (p < 0.001) as compared to normal renal tissues, but their expression was reduced or absent in the tumor core. High-grade and high-stage tumors exhibited stronger PTX3 and IL-6 expression and lower levels of cell cycle inhibitors (p < 0.001). Patients with elevated serum IL-6 levels had significantly lower 5-year cancer-specific survival (p < 0.005) and shorter progression-free survival (p < 0.001). Conclusions: Our findings suggest that peritumoral tissue in RCC exhibits a senescent and proinflammatory phenotype that may support tumor progression. PTX3 and IL-6 are potential biomarkers of disease severity and prognosis. Targeting inflammaging pathways could offer new therapeutic strategies for RCC, particularly in aggressive disease forms.