Background: Presurgical clinical trial design allow for pharmacodynamically relevant tissue collection that can inform regarding drivers of tumor biology. An unmet need is the ability to identify tumors that may respond to immunotherapy and the underlying mechanism of immune infiltration. Methods: This single arm phase II study was designed to test efficacy and safety of presurgical sunitinib treatment in metastatic RCC, and to identify drivers of tumor biology. Patients (pts) with metastatic RCC and a resectable primary received sunitinib 50mg PO daily for four weeks, and underwent restaging. If deemed a candidate, pts underwent cytoreductive nephrectomy (CN) during their second cycle of sunitinib, with last dose administered the day before surgery. Pts were restaged postoperatively and continued on sunitinib if no progressive disease was seen. Genomic and histological characteristics of RCC were evaluated for correlations between response and biological features. Results: Between June 2008 and October 2011, 50 pts were enrolled. 41 underwent CN. Seven pts showed refractory disease and were not considered surgical candidates. No sunitinib related perioperative toxicities were observed. Six pts progressed on first postoperative imaging studies, with three patients developing new brain metastases. Median progression free survival (PFS) was 8.6 months, and overall survival was 38 months. Objective response rate was 30 percent with 2 pts demonstrating a complete response. Analysis on 39 pts showed HIF1a staining was significantly associated with PFS (p = 0.023*, univariate Cox model), with a hazard ratio (HR) of 1.028 (95% CI, 1.004-1.053). This association remained significant in a multivariate Cox model adjusting for age and gender (p = 0.019*). In addition, HIF1a correlated with multiple immune markers (CD8, CD45RO, PD1, Treg, CD68, and LAG3). Analysis of genomic correlates is ongoing. Conclusions: Presurgical sunitinib therapy in RCC is safe and efficacious. HIF1a staining is associated with shorter PFS, and with increased immune infiltration. Tissue HIF1a should be explored as a marker, and studied mechanistically as a driver of the immune microenvironment in RCC. Clinical trial information: NCT00715442