Perioperative Systemic Therapy in Localized Renal Cell Carcinoma: Current Evidence and Future Directions

Localized renal cell carcinoma (RCC) carries a substantial risk of recurrence after nephrectomy, particularly in patients with adverse pathological features. Perioperative systemic therapy aims to eradicate micrometastatic disease. This review summarizes current evidence for neoadjuvant, adjuvant, and perioperative strategies in localized RCC, and outlines how emerging biological insights may reshape trial design and clinical practice. We conducted a narrative, non-systematic review of phase II-III studies and conference presentations through August 2025, examining trials that reported disease-free or recurrence-free and overall survival, perioperative feasibility, and translational endpoints, with data cross-checked against full texts and meeting abstracts. Adjuvant pembrolizumab improves disease-free and overall survival in selected high‑risk clear‑cell RCC and is now standard of care, whereas results from vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and mTOR inhibitors have been inconsistent across trials, with most studies failing to demonstrate a survival benefit. Neoadjuvant immune checkpoint inhibitor (ICI), TKI, and immuno-oncology-tyrosine kinase inhibitor (IO-TKI) regimens are feasible and generally safe without delaying surgery; radiographic shrinkage is modest, but clinically meaningful surgical facilitation has been observed, particularly in cases with inferior vena cava tumor thrombus. To date, no randomized neoadjuvant trial has improved disease-free or overall survival, and the only completed phase III perioperative trial (PROSPER RCC) did not improve recurrence‑free survival, underscoring the need to better understand the optimal duration, timing, and patient selection for perioperative immunotherapy. Emerging biomarkers, including circulating KIM-1, ctDNA, and CD39⁺ and TCF-1⁺ CD8 states, may enable risk stratification and treatment tailoring but remain exploratory. Overall, adjuvant pembrolizumab is practice-changing for high-risk clear-cell RCC, while neoadjuvant and perioperative approaches remain investigational. Advancing the field will require biomarker‑driven patient selection supported by adaptive or platform trial designs capable of rapidly evaluating multiple strategies.