Preoperative VEGFR‐TKI Plus ICI Therapy Facilitates 3D‐Guided Cytoreductive Nephron‐Sparing Surgical Feasibility and Immune Remodeling in Advanced Renal Cell Carcinoma

ABSTRACT Systemic therapy combining VEGFR‐tyrosine kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICIs) has reshaped first‐line care in advanced clear cell renal cell carcinoma (ccRCC). Its utility in the preoperative setting to facilitate 3D‐guided cytoreductive nephron‐sparing surgery (cNSS) and its accompanying immunologic remodeling remain insufficiently defined. Sixty patients with advanced ccRCC were prospectively enrolled and stratified into three cohorts: Group 1 (preoperative TKI‐ICI therapy followed by surgery), Group 2 (upfront surgery followed by systemic therapy), and Group 3 (systemic therapy alone). Endpoints included perioperative safety, feasibility of cNSS, renal function, radiographic response, survival, and tumor immune microenvironment remodeling by histopathology and multiplex immunofluorescence, assessing heterogeneity of tertiary lymphoid structures (TLSs). All surgical planning used CT‐based 3D reconstruction for vascular/collecting‐system mapping. Despite greater anatomical complexity, Group 1 showed superior intraoperative metrics, lower grade ≥ III complications (15% vs. 35%), reduced blood loss (median 150 vs. 280 mL), and shorter warm ischemia (18 vs. 28 min; all p ≤ 0.02) and achieved a higher cNSS rate (80% vs. 50%; p = 0.03) with R0 resection in 95%. Renal function decline was attenuated (ΔeGFR 12 months −10.2 ± 6.3 vs. −18.8 ± 8.1 mL/min/1.73 m 2 ; p = 0.01). Radiographic ORR was 55% preoperatively. Survival favored Group 1 versus Group 3 (PFS, HR: 0.286, and p = 0.011; OS, HR: 0.185, and p = 0.003) and showed an OS advantage versus Group 2 (HR: 0.298 and p = 0.043). Tumor microenvironment analysis demonstrated increased CD8 + /CD20 + infiltration, higher TLSs density and maturity, greater necrosis, and stromal reorganization, indicating on‐treatment immune activation potentially underpinning clinical benefit. Safety was acceptable with manageable irAEs and standardized TKI/ICI perioperative holds. In conclusion, preoperative VEGFR‐TKI + ICI integrated with CT‐based 3D‐guided robotic cytoreduction is feasible and safe, expands candidacy for cNSS, preserves renal function, and improves survival in advanced ccRCC while inducing robust TLSs‐linked immune remodeling.