Clear cell renal cell carcinoma (ccRCC) exhibits pronounced heterogeneity across WHO histological grades, yet systematic single-cell multi-omics studies characterizing these transitions remain limited. We integrated scRNA-seq and scATAC-seq data across ccRCC WHO grades to establish a multi-omics framework encompassing tumor cells and immune populations. Using pseudotime trajectory analysis and machine learning ensembles, we developed a prognostic signature (CBG) from core nodes of transcriptional regulatory networks. We found that in tumor cells, epigenetic alterations consistently precede metabolic reprogramming and invasive adaptation. CD8+ T cell exhaustion followed a trajectory shifting from IRF7- to ZNF683-regulated states, while monocytes differentiated toward M1 and M2 macrophages orchestrated by NFIC/IL1B and CEBPD/GLI2. Intercellular communication networks showed a temporal progression from inflammation, through vascular remodeling, to immunosuppression dominance. The CBG signature demonstrated robust performance in independent cohorts, identifying SLC11A1 and SH3YL1 as antagonistic survival determinants. This study elucidates the dynamic molecular and immunological mechanisms underlying ccRCC grade progression, providing a robust framework for subtype-specific prognostication and precision therapeutic targeting
Liu, R., Shi, Y., Xiao, Y., Ren, B., Li, L., Qi, B., Li, T., Zhang, Y., Gao, J.
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