Int Urol Nephrol. 2026 Jul 10. doi: 10.1007/s11255-026-05235-9. Online ahead of print.
ABSTRACT
PURPOSE: This study aimed to characterize ferroptosis heterogeneity within the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC) and investigate its impact on immune remodeling and clinical prognosis.
METHODS: Single-cell transcriptomic analysis was performed using the GSE159115 dataset to classify cell phenotypes. Functional enrichment, immune infiltration, and pathway analyses (GSEA) were conducted. Validation utilized the GSE312695 and TCGA-KIRC cohorts.
RESULTS: ccRCC tissues were enriched with ferroptosis-resistant cells, whereas normal tissues contained ferroptosis-sensitive cells. Eight core genes regulating ferroptosis susceptibility were identified. Resistant cells established an immunosuppressive “immune desert” TME, with significant suppression of T-cell and macrophage pathways. The ferroptosis resistance signature demonstrated generalizability across cohorts, and medium-high resistance scores showed a trend toward poorer survival in specific subgroups, although overall survival differences did not reach statistical significance.
CONCLUSION: Ferroptosis heterogeneity contributes to ccRCC progression by shaping an immunosuppressive TME. The identified molecular features offer potential targets for therapy and highlight the complexity of utilizing ferroptosis signatures for prognostic assessment in ccRCC.
PMID:42430097 | DOI:10.1007/s11255-026-05235-9
