Immunotherapy has been significantly advanced by the use of immune checkpoint inhibitors (ICIs). ICIs have shown remarkable therapeutic benefits in several cancer types, especially in advanced metastatic stages. However, despite durable responses, only a small proportion of patients benefit from ICI therapy for unclear reasons. We have recently reported that in response to ICI, the host generates systemic pro-tumorigenic effects which contribute to the aggressiveness of tumor cells. These findings can explain, at least partially, drug resistance and tumor spread following ICI therapy. Therefore, uncovering the pro-tumorigenic effects of immunotherapy may reveal novel strategies to improve ICI therapy responses and circumvent cancer metastasis. At the center of this proposal, we have recently found that under certain circumstances ICI resistant tumor outgrowth lead to brain metastasis following such therapy. We hypothesized that these effects are associated with the disruption of the blood-brain-barrier (BBB) in response to the therapy. In this proposed research, we aim to uncover the mechanisms underlying host-mediated induction of brain metastasis in the ICI-treated resistant tumor microenvironment. We will focus on the disruption of BBB following ICIs and the potential cellular and molecular pathways that contribute to this process. Lastly, we will study ways to inhibit the risk for brain metastasis and ask for its clinical impact. Deciphering the nature of brain metastasis in tumors resistant to ICI therapy is essential for optimizing treatment and minimizing this potential side effect.