Integrative Analysis of Immune- and Metabolism-Related Genes Identifies Robust Prognostic Signature and PYCR1 as a Carcinogenic Regulator in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is distinguished by metabolic irregularities and unique immunological profiles. Nevertheless, the comprehensive examination of immune and metabolic attributes within the tumor microenvironment of ccRCC remains inadequately elucidated. In this study, we identified two distinct molecular subtypes (C1 and C2) of ccRCC using the non-negative matrix factorization (NMF) algorithm. Utilizing univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, we developed a prognostic signature comprising eight immune- and metabolism-related genes (IMRGs) associated with the tumor microenvironment. The validation of this signature was performed using both testing and entire datasets. A nomogram was developed using IMRGs prognostic signature and various clinical parameters, including age and TNM stage. We also performed the in vitro experiments to validate the carcinogenic role of PYCR1 in ccRCC cells. Subtype C1 exhibited a more favorable prognosis and higher levels of immune cell infiltration compared to subtype C2. The AUCs of the nomogram at 1-, 3-, and 5-year intervals (AUC = 0.874, 0.820, and 0.794) were slightly higher than those of the IMRGs signature alone (AUC = 0.773, 0.755, and 0.764). The association between risk score and immune checkpoint expressions, immunophenoscore (IPS), and microsatellite instability (MSI) collectively predicted treatment efficacy accurately. Additionally, in vitro experiments confirmed the involvement of PYCR1 in promoting the aggressive behaviors of ccRCC cells, as evidenced by reduced proliferation, invasion, and enhanced apoptosis upon PYCR1 knockdown. In conclusion, the IMRGs signature shows promise in predicting prognostic risk, assessing the effectiveness of immunotherapy, and tailoring treatment for ccRCC patients.