The recruitment of vascular endothelial cells from the tumor microenvironment (TME) to promote angiogenesis plays key roles in the progression of renal cell carcinoma (RCC). The potential impact of immune cells in the TME on RCC angiogenesis, however, remains unclear. Here, we found that recruitment of mast cells resulted in increased RCC angiogenesis in both in vitrocell lines and in vivo mouse models. Mechanistic analyses revealed that RCC recruited mast cells by modulating PI3K-AKT-GSK3β-AM signaling.  A clinical survey of human RCC samples also showed that higher expression of the PI3K-AKT-GSK3β-AM signaling pathway correlated with increased angiogenesis. Interruption of PI3K-AKT-GSK3β-AM signaling via specific inhibitors led to decreased recruitment of mast cells, and targeting this infiltrating mast cell-related signaling via an AKT-specific inhibitor suppressed RCC angiogenesis in xenograft mouse models. Together, these results identified a novel role of infiltrating mast cells in RCC angiogenesis and metastasis and suggest a new strategy for treating RCC by targeting this newly identified signaling pathway.Oncogene advance online publication, 23 January 2017; doi:10.1038/onc.2016.442.