When cancer cells metastasize to the brain, the diagnosis becomes terminal. In melanoma brain metastasis, patients are only given months to live. There is an urgent need to develop treatment strategies to improve clinical outcomes for these patients. Although immunotherapy has been successfully used to treat some types of cancers, its effectiveness is limited in many solid tumors, including brain metastasis. One reason for this is due to the accumulation of myeloid cells in the tumor. These myeloid cells come from bone marrow, and enter the circulation when tumors produce recruitment signals into the blood. One of the main functions of these myeloid cells is to suppress the killing activity of T cells, allowing the tumors to grow while evading the body’s natural immune system. In the brain, there are specialized myeloid cells called microglia. In brain tumors, these microglia are thought to have both unique and shared functions to the circulating myeloid cells. Therefore, a better understanding of these microglia and how they may contribute to brain tumor progression will lead to the development of new therapies. This study will investigate a biological signaling pathway that is found to be activated in microglia as a response to invading cancer cells. This pathway is part of the natural immune response exerted by microglia in many other nervous system diseases, such as Alzheimer’s and multiple sclerosis. In these other diseases, the activated microglia play a role in resolving inflammation, which has beneficial effects by reducing damage to the local organ. In cancer, however, this has the opposite effect and protects the tumor, allowing it to grow unchecked. In this study, we propose to investigate this pathway and its involvement in brain tumor progression. Completion of this project will establish targeting of microglia as a new therapeutic approach, in combination with immunotherapies, for brain metastasis patients.