Brain metastases represent the most common intracranial tumor in adults associated with poor prognosis and median survival of only a few months. Despite current success in the development of targeted or immuno-therapies against different cancer entities, those strategies are ineffective against brain metastases. Hence, treatment options for brain metastasis patients largely remain limited to surgical resection and radio- and/or chemotherapy. This paucity can in part be attributed to the immune-privileged status of the brain where the blood brain-barrier restricts the entry of blood-borne immune cells. However, recent insights into the immune landscape of primary brain cancers indicate that tumor progression leads to an infiltration of blood-borne immune cells into the brain. We employ a comprehensive set of experimental brain metastasis models to characterize the immune landscape of brain metastases from different primary cancer entities at distinct disease stages and in response to radiotherapy. Our data indicate that brain metastases induce massive infiltration of myeloid and lymphoid cell populations into the central nervous system. This leads to the establishment of a dynamic and highly complex tumor microenvironment that affects tumor progression and therapy response. Fractionated whole-brain radiotherapy leads to enhanced infiltration of blood-borne myeloid and lymphoid cells. Transcriptome analysis of brain-resident and recruited myeloid cells indicate a switch from a proinflammatory towards an immune-suppressive environment at advanced disease stages. Importantly, radiotherapy was found to induce gene signatures that are associated with proinflammatory innate immune responses that could revert the establishment of an immune-suppressive environment. Consequently, radiotherapy might sensitize brain metastases towards immuno-therapies. Our goal is to identify pathways or molecular targets that are induced by radiotherapy in the tumor microenvironment to overcome resistance against immuno-therapy. In this project, we seek to test strategies to maintain or induce proinflammatory immune responses for improved targeted or immuno-therapies against brain metastasis. Citation Format: Michael Schulz, Katja Niesel, Anna Salamero Boix, Woon Hyung Chae, Birgitta Michels, Alexander Schaeffer, Maja Strecker, Tijna Alekseeva, Stefan Stein, Henner Farin, Franz Roedel, Patrick Harter, Karlheinz Plate, and Lisa Sevenich. Effects of ionizing radiation on brain metastasis-associated inflammation and its implication for immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A111.