Natural Products in Clear Cell Renal Cell Carcinoma: Rewiring the VHL-HIF Axis, Metabolic Plasticity, and Tumor-Immune Interactions.

Clear cell renal cell carcinoma (ccRCC) is driven by von Hippel-Lindau (VHL) tumor suppressor loss and persistent activation of hypoxia-inducible factors (HIFs), which coordinately regulate angiogenesis, metabolic reprogramming, redox balance, and tumor-immune interactions. Although immune checkpoint inhibitors and vascular endothelial growth factor-targeted therapies have improved outcomes, resistance remains common due to adaptive network plasticity. Selected natural products have been reported to exhibit multitarget regulatory activities that may influence interconnected oncogenic pathways. This review highlights how compounds such as curcumin, resveratrol, quercetin, and epigallocatechin-3-gallate modulate the VHL-HIF axis, disrupt metabolic and redox homeostasis, and influence tumor-immune system interactions in ccRCC. We propose a system-level framework in which natural products enhance therapeutic sensitivity; however, further validation is required for clinical translation.