Project Summary / Abstract: Cancer is a leading cause of death, but recent emergence of immunotherapies including the immune checkpoint inhibitors has offered promising new cancer treatment options. It is also evident that tumor immunity is highly complex and incompletely understood. The better understanding of tumor immune regulation may lead to identification of additional targets for cancer immunomodulatory therapy. In this study we will investigate the mechanism by which the cell surface receptor protein LRP5 regulates NK cell activities and tumor immunity. In our preliminary studies, we found that loss of LRP5 led to increased activation of NK cells independently of β-catenin stabilization despite LRP5 is involved in β-catenin regulation in other cells. Thus, we hypothesize that LRP5 regulates NK activation via previously uncharacterized mechanisms. Because genetic inactivation of LRP5 in NK cells suppresses tumor progression accompanied with enhanced NK activities in mice, this new mechanism is potentially of important clinical implications. Our preliminary results suggest that LRP5 may function as a fatty acid transporter leading to regulation of mTROC1 activity. In this application, we will carry out comprehensive in vitro and in vivo investigations to characterize this new mechanism for LRP5 and to determine the roles of this new mechanism in NK biology and tumor surveillance.