Obesity-driven metabolic reprogramming and immune dysfunction in renal cancer

Renal cell carcinoma (RCC), specifically clear cell renal cell carcinoma (ccRCC), is a metabolic tumor wherein the physiological state of the host is central to tumor development, progression, and therapeutic resistance. Obesity has emerged as one of the major risk factors associated with RCC; however, its impact on RCC is more complex than simply the accumulation of excess body fat. Obesity transforms the renal tumor microenvironment through metabolic rewiring and alterations in inflammation, vasculature, and anti-tumor immunity. The expansion of adipose tissue in obesity alters the renal microenvironment through the production of fatty acids, adipokines, and cytokines in a manner that not only supports tumor growth but also promotes immunosuppression. Increased levels of leptin, resistin, IL-1β, IL-6, IL-8, and VEGF - together with decreased levels of adiponectin and omentin-1 - promote angiogenesis, stromal remodeling, recruitment of myeloid cells, and evasion of immune checkpoint inhibition. These obesity-driven factors interact with the intrinsic metabolism of ccRCC cells, including lipid accumulation, glycolysis, hypoxic signaling, and metabolic plasticity. Furthermore, obesity reshapes the immune environment through recruitment of MDSCs, polarization of TAMs, dysfunction of DCs, neutrophil-mediated immunosuppression, T cell exhaustion, and increased abundance of regulatory T cells, reinforcing an immunosuppressive state. These effects of obesity in RCC are particularly relevant in the context of the obesity paradox, wherein obesity has been associated with improved treatment outcomes, which are not uniformly observed across RCC cohorts. These differences may reflect the limitations of body mass index as a biological indicator of obesity, together with variations in systemic inflammation, body composition, and treatment context. Here, we summarize current knowledge on obesity-driven immunometabolic rewiring in RCC and outline key priorities for the field, including obesity-relevant preclinical models, biomarkers of visceral adiposity and systemic inflammation, and clinical trials targeting immunometabolism.