Lipid dysregulation in renal cancer: Drivers of tumor growth and determinants of treatment-induced toxicity.

BACKGROUND

Clear cell renal cell carcinoma (ccRCC) exhibits a distinctive metabolic signature marked by the excessive buildup of cholesterol and neutral lipids. This phenotype stems largely from the loss of the von Hippel-Lindau (VHL) tumor suppressor and the resulting stabilization of hypoxia-inducible factors (HIFs). The altered lipid environment enables ccRCC cells to sustain growth, evade immune surveillance, and withstand contemporary systemic therapies. Increasing evidence indicates that similar disturbances in lipid metabolism contribute to kidney injury during cancer treatment, suggesting that dysregulated cholesterol handling represents a shared pathologic foundation linking tumor progression with therapy-induced nephrotoxicity.

SCOPE OF REVIEW: This review brings together mechanistic, preclinical, and translational findings that illuminate how defective cholesterol regulation-particularly diminished ABCA1-mediated efflux promotes tumor aggressiveness while heightening renal vulnerability to radiation therapy, tyrosine kinase inhibitors (TKIs), and immune checkpoint inhibitors (ICIs). We examine lipid droplet dynamics, cholesteryl ester biology, and mitochondrial perturbations in ccRCC cells and renal parenchymal cells exposed to therapeutic stress.

MAJOR

CONCLUSIONS

Across ccRCC therapies, lipid accumulation drives renal injury, with lipid-sensitive cells, particularly podocytes, undergoing cytoskeletal and slit-diaphragm disruption, proteinuria, and progressive glomerular damage in response to cholesterol overload, oxidative stress, and inflammatory signaling. Within the tumor, suppression of ABCA1 perpetuates lipid droplet expansion, reinforces resistance to therapy, and intensifies metabolic strain within the microenvironment.

FUTURE DIRECTIONS: Restoring cholesterol balance through LXR agonists, cyclodextrins, or strategies that enhance ABCA1 function holds promise for limiting renal toxicity while simultaneously impairing tumor survival mechanisms. Advances in lipidomics, metabolic imaging, and biomarker-driven stratification may facilitate precision approaches that integrate metabolic correction with effective oncologic care.