Abstract
Brain metastases (BrM) develop in 20-40% of patients with advanced cancer. They mainly originate from lung cancer, melanoma, breast cancer, and renal cell carcinoma, and are associated with a poor prognosis. While patients with BrM traditionally lack effective treatment options, immunotherapy is increasingly gaining in importance in this group of patients, with clinical trials in the past decade demonstrating the efficacy and safety of immune checkpoint blockade in BrM originating from specific tumor types, foremost melanoma. The brain is an immune-specialized environment with several unique molecular, cellular, and anatomical features that affect immune responses, including those against tumors. In this review we discuss the potential role that some of these unique characteristics may play in the efficacy of immunotherapy, mainly focusing on the lymphatic drainage in the brain and the role of systemic anti-tumor immunity that develops due to the presence of concurrent extracranial disease in addition to BrM.