Cancer Cachexia in Advanced Renal Cell Carcinoma: From Molecular Mechanisms to Prognostic Assessment

Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle loss, affecting 30-60% of patients with advanced renal cell carcinoma (RCC). It significantly impacts treatment tolerance, quality of life, and prognosis, yet its diagnosis and management remain challenging due to fragmented RCC-specific evidence, particularly in the era of immune checkpoint inhibitor (ICI)-based therapy. The pathogenesis involves persistent systemic inflammation, metabolic reprogramming, and tumor-host interactions. The IL-6/STAT3 and TNF-α/NF-κB pathways are central to muscle catabolism, while tumor-derived mediators such as GDF15 and PTHrP, along with mitochondrial dysfunction, further drive cachexia progression. For prognostic assessment, CT-derived skeletal muscle mass evaluation combined with systemic inflammatory and nutritional biomarkers-including neutrophil-to-lymphocyte ratio (NLR), modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), and cachexia index (CXI)-has improved risk stratification in advanced RCC. Preclinical and emerging clinical data suggest that targeted therapies may partially attenuate cachexia by modulating inflammatory signaling, while multimodal interventions integrating nutritional support and exercise rehabilitation remain the cornerstone of management. Novel strategies, such as inhibition of the GDF15/GFRAL axis, are under active investigation. Future research should prioritize identification of early biomarkers, standardization of cachexia assessment, and prospective evaluation of cachexia-directed interventions in the immunotherapy era. Integrating cachexia assessment into routine practice may ultimately enable personalized treatment and improve long-term outcomes for patients with advanced RCC.