Biomarkers in Clear Cell Renal Cell Carcinoma: From Biological Association to Clinical Decision-Making.

Therapeutic options in renal cell carcinoma (RCC) have expanded rapidly, including adjuvant pembrolizumab, HIF-2α-directed therapy, and multiple effective first-line combinations for metastatic clear-cell RCC (ccRCC), yet treatment selection remains largely clinicopathologic. This review evaluates biomarkers at three clinical decision points: characterization of an indeterminate renal mass; recurrence-risk assessment and adjuvant treatment selection after nephrectomy; and first-line regimen selection in metastatic ccRCC. DNA-methylation classifiers and carbonic anhydrase IX-targeted [89Zr]Zr-girentuximab PET/CT can improve characterization of selected renal tumors, but neither replaces histopathology in routine practice. After nephrectomy, elevated plasma kidney injury molecule-1 (KIM-1) and detectable circulating tumor DNA (ctDNA) identify patients at higher risk of recurrence; however, low tumor shedding limits ctDNA sensitivity, so a negative result does not exclude molecular residual disease or justify adjuvant de-escalation; neither biomarker is validated to direct surveillance, adjuvant therapy, or treatment escalation. In metastatic ccRCC, PD-L1 expression, tumor mutational burden, and individual genomic alterations do not reliably distinguish patients who should receive dual immune-checkpoint blockade from those who should receive an immune-checkpoint inhibitor plus a VEGFR tyrosine kinase inhibitor. Transcriptomic states, myeloid composition, and spatial immune organization provide more detailed treatment-relevant biology, but no prospective comparative trial has shown that biomarker-guided regimen selection improves outcomes. Clinical implementation will require standardized assays, independent multicenter validation, and prospective trials powered to test biomarker-by-treatment interactions.