Renal cell carcinoma: Molecular mechanisms and emerging therapeutic strategies

Renal cell carcinoma (RCC) poses a persistent clinical challenge, mainly due to its resistance to conventional therapies. With increased detection through modern imaging, more cases are being identified early, yet advanced or metastatic RCC remains challenging to treat. A deeper understanding of RCC’s molecular underpinnings has reshaped treatment strategies. Central to this is the von Hippel-Lindau (VHL) – hypoxia-inducible factor (HIF) – vascular endothelial growth factor pathway, which drives tumor angiogenesis, particularly in clear cell RCC. Disruption of this axis has been crucial in designing targeted therapies. In addition, pathways such as mammalian target of rapamycin and metformin (MET) play important roles in tumor growth and progression in certain subtypes. Immunotherapy has also redefined outcomes, especially with the success of immune checkpoint inhibitors, which help the body’s immune system recognize and fight cancer cells. Combining immunotherapy with targeted agents has become standard in many treatment settings due to their complementary effects. However, challenges remain – such as drug resistance and a lack of reliable biomarkers to guide therapy choices. Recently, HIF-2α inhibitors like belzutifan have emerged as promising precision treatments, especially in tumors with VHL mutations. As research continues, integrating molecular insights with clinical practice holds the potential to improve survival and quality of life for patients living with RCC.