Melanoma is the most aggressive form of skin cancer. One of the most common and devastating complications of melanoma is the spread of cancer to the brain, which is called melanoma brain metastasis. The survival of patients with melanoma brain metastasis used to be very short. However, new treatments have been developed that can control melanoma brain metastases, including stereotactic radiosurgery, immune therapy, and targeted therapy. Despite these advances, many patients eventually develop resistance to these treatments. In this project, we will focus on the impact of tumor metabolism on metastatic progression of melanoma. Cancer cells have the capacity to modify their metabolism to adapt to different environments in order to metastasize and grow in organs beyond where they originated. We believe that these different metabolic pathways (such as pathways involved in glucose and lipid production and oxidative stress) can be potentially targeted to develop novel therapeutics and to also improve the response of melanoma tumors to current immune and targeted therapies. In the current project, we will use melanoma cell lines in which expression of major genes involved in these pathways have been silenced. We will then inject these cells into the brain of mice (intracranial injection) and will study how inhibiting each of these pathways affects the growth and immune characteristics of melanoma brain tumors in mice. By targeting each individual pathway, we will be able to gain a better understanding of the role they play in development and growth of brain metastasis and use that information towards building new therapies. These studies will provide critical insights into potential therapeutic targets, ultimately offering hope for more effective treatments in patients with melanoma brain metastasis.