Multi-omics insights into tumor grade progression in clear cell renal cell carcinoma: from molecular mechanisms to precision therapeutics.

Clear cell renal cell carcinoma (ccRCC) can transition from indolent, low-grade lesions to high-grade, lethal disease through a layered cascade of genomic, epigenomic, metabolic, and immune remodeling. The initiating event in ∼90% of ccRCC is loss of chromosome 3p, enabling biallelic inactivation of VHL and frequent co-loss of chromatin regulators PBRM1, BAP1, and SETD2. The order and combination of genetic alterations shape distinct evolutionary trajectories in ccRCC. PBRM1 loss, observed in approximately 55% of cases, is linked to angiogenic, initially low-grade tumors that may later progress to higher-grade disease. In contrast, BAP1 loss (∼15%) drives early high-grade, inflammatory, immune-enriched phenotypes associated with aggressive behavior and worse prognosis. Progression is further shaped by structural and copy-number events including, chromothripsis coupling 3p loss with 5q gain, and recurrent 9p and 14q losses and 8q gain further promote cell-cycle dysregulation, genomic instability, and metastatic competence. Functionally, VHL loss stabilizes HIF-2α, driving VEGF signaling and Carbonic Anhydrase IX (CA9) expression and coupling pseudohypoxia to metabolic reprogramming and redox protection (glutathione/SLC7A11). Proteogenomic and metabolomic studies further highlight nutrient addiction with GLUT1/ASCT2 upregulation and a stress-resistant metabolic shield linked to grade and therapy resistance. Single-cell and spatial atlases place these programs in anatomic setting. They show that invasive fronts with high epithelial-mesenchymal transition (EMT) activity co-localize with myeloid and regulatory T-cell niches dominated by IL-1β, NF-κB, IL-10, STAT3, and TGF-β, along with exhausted CD8