Abstract
The development of immunotherapy has changed the treatment landscape of advanced kidney renal clear cell carcinoma (KIRC), offering patients more treatment options. Cuproptosis, a novel cell death mode dependent on copper ions and mitochondrial respiration has not yet been studied in KIRC. We assembled a comprehensive cohort of The Cancer Genome Atlas (TCGA)-KIRC and GSE29609, performed cluster analysis for typing twice using seven cuproptosis-promoting genes (CPGs) as a starting point, and assessed the differences in biological and clinicopathological characteristics between different subtypes. Furthermore, we explored the tumor immune infiltration landscape in KIRC using ESTIMATE and single-sample gene set enrichment analysis (ssGSEA) and the potential molecular mechanisms of cuproptosis in KIRC using enrichment analysis. We constructed a cuproptosis score (CUS) using the Boruta algorithm combined with principal component analysis. We evaluated the impact of CUS on prognosis, targeted therapy, and immunotherapy in patients with KIRC using survival analysis, the predictions from the Cancer Immunome Atlas database, and targeted drug susceptibility analysis. We found that patients with high CUS levels show poor prognosis and efficacy against all four immune checkpoint inhibitors, and their immunosuppression may depend on TGFB1. However, the high-CUS group showed higher sensitivity to sunitinib, axitinib, and elesclomol. Sunitinib monotherapy may reverse the poor prognosis and result in higher progression free survival. Then, we identified two potential CPGs and verified their differential expression between the KIRC and the normal samples. Finally, we explored the effect of the key gene FDX1 on the proliferation of KIRC cells and confirmed the presence of cuproptosis in KIRC cells. We developed a targeted therapy and immunotherapy strategy for advanced KIRC based on CUS. Our findings provide new insights into the relationship among cuproptosis, metabolism, and immunity in KIRC.