Our immune response is equipped with potent anti-tumor mechanisms that can sense and destroy tumors. However, tumor cells have evolved sophisticated mechanisms that evade immune responses by shielding the tumor environment from pro-inflammatory signals. Macrophages are important white blood cells that can sense pathogens and communicate with our adaptive immune responses to eliminate infections. In contrast, in the tumor environment a specific type of macrophages called tumor-associated macrophages accumulate within the tumor and provide protection to the tumor by secreting anti-inflammatory molecules and mopping up pro-inflammatory signals that can recruit other immune cells such as killer T-cells that can kill tumor cells and stop tumors from growing and spreading. Certain childhood cancers such as sarcoma accumulate a large number of tumor associated macrophages in their tumors. These cells contribute to suppressing our immune system and increasing cancer progression. In addition, tumor associated macrophages can also reduce the effectiveness of frontline therapies. In this proposal we aim to explore a novel mechanism by which our innate immune system can block the activity of tumor associated macrophages by inhibiting a protein called MARCO. MARCO is a scavenger protein found on the surface of macrophages within the tumor. MARCO allows tumor cells to evade detection by our immune system.  Based on these preliminary findings we aim to further understand how our anti-tumor immune responses suppress the levels of MARCO on the surface of macrophages and increase anti-tumor immunity. By deciphering the signals that control how MARCO is regulated by our innate immune system we can harness this information to develop new therapeutic interventions in child cancers.