Vascular abnormalities and immune suppressive characteristics of the tumour microenvironment represent a major obstacle in cancer immune therapy. Abnormal tumour vessels form a barrier that prevents effective blood flow, drug delivery and immune destruction. Regulator of G protein signaling 5 (RGS5) is a key regulator of angiogenic vessel remodelling in cancer. Specifically, RGS5 is highly upregulated in tumour pericytes. Pericytes are unique mural cells which share with vascular smooth muscle cells (vSMC) the ability to contract and support endothelial cells of the microvasculature. Fewer and loosely attached pericytes are a feature of leaky tumour blood vessels. Using a mouse model of neuroendocrine pancreatic cancer (RIP1-Tag5), we have previously shown that loss of RGS5 “normalizes” blood vessels by correcting structural and functional vessel abnormalities which in turn enhances anti-cancer therapy (Hamzah et al, Nature 2008). How RGS5 expression regulates vascular integrity, however, is at present unknown. Here we demonstrate in tumour-bearing RGS5 gene-deficient mice that RGS5 controls alignment of endothelial cells and pericytes within the vascular bed. Importantly, improved vessel integrity in RGS5-deficient tumours correlates with a more contractile and less synthetic phenotype of pericytes as demonstrated by increased expression of contractile vSMC markers such as caldesmon and calponin, and reduced collagen 1 expression (Johansson-Percival et al, Cell Reports 2015). In contrast, overexpression of RGS5 in tumour vasculature abolishes pericyte maturation and vessel integrity. Our current data thus provide evidence that RGS5 levels correlate with so far unrecognized pericyte phenotype switching in solid tumours. Controlling RGS5 expression may be used therapeutically to normalize tumour vessels which has profound implications for chemo- and immunotherapy.