The release of certain micro RNAs (miRs) into the tumor microenvironment was shown to promote cancer progression. Our preliminary work indicates that miR-146a targets the TRAF6/TNF axis and that miR-146a deficient mice experience reduced growth of pulmonary melanoma metastases and survive longer. Additionally we found expression of miR-146a in human melanoma and breast cancer tissues. To better understand and manipulate the role of miR-146a in the tumor microenvironment, we will address the following: 1. The impact of miR-146a on different cell types of the tumor microenvironment in melanoma and breast cancer models with respect to phenotype, motility and invasive properties will be determined. 2. The signaling events elicited by the lack of miR-146a in tumor and stroma cells will be characterized. A particular focus will be on the levels of miR-146a target genes including TRAF6, IRAK1, IRAK2 and STAT1 and others. The impact of the STAT1/IFN-γ axis, which is negatively regulated by miR-146a, on tumor cell motility will be analyzed. 3. Antagomir-based targeting of miR-146a to enhance IFN-γ production and improve anti-PD1 based immunotherapy will be tested for its anti-tumor effects. The planned studies will deliver novel insights into the role of miR-146a in the tumor microenvironment and potentially allow intervening with tumor progression in vivo.