Project Summary Endothelial cells play an important role in regulating several aspects of the tumor microenvironment. Our lab has identified miR-103 as a radiation inducible miR that exacerbates DNA damage and has an overall tumor suppressive effect in preclinical tumor models. We also discovered that this miR targets a DNA sensor three prime exonuclease TREX1. This enzyme has important roles in preventing type I interferon signaling and autoimmune activation. Our pilot studies show that miR-103 disruption of TREX1 leads to an increase in cellular and molecular mediators of inflammation in tumors. In this proposal, we will investigate A) How this miR-103 pathway in the tumor cells affects the immune microenvironment? B) What are the relative contributions of TREX1 in DNA damage dependent and independent signaling in the vasculature and finally C) How to genetically and target TREX1 pathway in vivo and exploit some of the pathways upregulated by the disruption of TREX1. Our studies will establish a new paradigm to provoke potent anti-tumor immunity using miR-mediated disruption of DNA repair, which enhances `danger signals' in the tumor microenvironment.