Obesity and renal cell carcinoma: Biological mechanisms and perspectives

Obesity, defined by body mass index (BMI), is an established risk factor for specific renal cell carcinoma (RCC) subtypes such as clear cell RCC, the most common RCC histology. Many studies have identified an association between obesity and improved survival after diagnosis of RCC, a potential "obesity paradox." Clinically, there is uncertainty whether improved outcomes observed after diagnosis are driven by stage, type of treatment received, or artifacts of longitudinal changes in weight and body composition. The biological mechanisms underlying obesity's influence on RCC are not fully established, but multiomic and mechanistic studies suggest an impact on tumor metabolism, particularly fatty acid metabolism, angiogenesis, and peritumoral inflammation, which are known to be key biological hallmarks of clear cell RCC. Conversely, high-intensity exercise associated with increased muscle mass may be a risk factor for renal medullary carcinoma, a rare RCC subtype that predominantly occurs in individuals with sickle hemoglobinopathies. Herein, we highlight methodologic challenges associated with studying the influence of obesity on RCC and review the clinical evidence and potential underlying mechanisms associating RCC with BMI and body composition.