Immunotherapy has repeatedly failed to improve outcomes in prostate cancer due to resistant immune cells and tumor inflammation. One approach that we pioneered is to use radiation to reprogram immunosuppressive immune cells and recruit new T cells. We can activate these recruited T cells by targeting pathways of inflammation that are correlated with poor survival in patients with lethal prostate cancer. In this project, we will test whether disruption of these pathways of inflammation can improve antitumor responses to immunotherapy in a mouse model of prostate cancer. We will then use knockout mice and purified immune cells to understand why inflammation is highly immunosuppressive in prostate cancer. Lastly, we will sequence individual immune cells to identify new immune-based targets in prostate cancer. The ultimate goal of this proposal is to develop new immune-based treatment strategies for patients with advanced prostate cancer, which is a critical unmet need in this disease.