Neoadjuvant therapies for clear cell renal cell carcinoma: review of current evidence and future applications

PURPOSE: Neoadjuvant systemic therapy for clear cell renal cell carcinoma (ccRCC) aim to improve oncological and survival outcomes in patients with high-risk disease. This review evaluates contemporary evidence for neoadjuvant and perioperative systemic therapies in ccRCC, with a focus on localised high-risk disease, venous tumour thrombus and metastatic or cytoreductive settings. METHODS: A review of the literature was performed using PubMed, Embase and Web of Science from database inception to February 2026. Eligible studies included randomised controlled trials, prospective and retrospective clinical studies, and translational research evaluating neoadjuvant therapies in RCC. Evidence was synthesised by therapeutic class, with emphasis on prospective trials and clinically relevant outcomes. RESULTS: Neoadjuvant TKIs demonstrate mild to moderate tumour shrinkage and reduction in tumour thrombus burden, with a resultant improvement in operative complexity and an increase in the number of patients eligible for surgical intervention. ICI monotherapy has shown limited efficacy in early-phase studies. However, combination ICI-TKI regimens report higher objective response rates on interval imaging, with tumour downstaging and encouraging early disease-free survival results. Perioperative complication rates appear acceptable across studies, with no consistent increase in surgical morbidity. However, discordance between radiological and pathological responses remains a limitation. Translational studies further highlight the potential role of immune profiling, genomic biomarkers, microbiome modulation and theranostic approaches, although prospective validation remains lacking. CONCLUSION: Neoadjuvant therapy in ccRCC is feasible and demonstrates promising early efficacy, particularly with combination regimens. However, current evidence is limited by heterogeneity and lack of long-term outcomes. Larger prospective trials incorporating translational endpoints are required to define optimal treatment strategies and establish survival benefit.