Hypoxia Signatures in Renal Cell Carcinoma: From HIF-Mediated Omics Remodeling to Precision Diagnostics

Abstract Renal cell carcinoma (RCC), particularly clear cell RCC (ccRCC), exhibits extensive metabolic, signaling, and microenvironmental remodeling associated with dysregulated VHL-HIF signaling. HIF activation in RCC may arise from VHL loss under normoxic conditions and from genuine tumor hypoxia due to inadequate oxygen availability; these states can converge on overlapping downstream programs but are biologically distinct. This review examines proteomic, phosphoproteomic, metabolomic, and emerging spatial and single-cell studies that characterize hypoxia- and VHL-HIF-associated molecular alterations in RCC. Particular emphasis is placed on protein-level changes in metabolism, angiogenesis, extracellular matrix remodeling, signaling, and immune regulation, as well as on how these measurements complement transcriptomic data. The review further distinguishes mechanistic molecular signatures from candidate diagnostic, prognostic, predictive, pharmacodynamic, and treatment-selection biomarkers. Evidence for circulating proteins and metabolites is discussed together with available measures of diagnostic performance, analytical validation, and clinical validation. Finally, the potential of integrated discovery and targeted mass-spectrometry approaches to support clinically useful multianalyte biomarker panel development is considered, while highlighting the challenges of tumor heterogeneity, assay reproducibility, cohort validation, and clinical utility.