The brain tumor microenvironment (TME) is a critical regulator of cancer progression in primary and metastatic brain malignancies. This review discusses the unique features of the brain TME, including brain-resident cell types, the blood-brain barrier (BBB), and the immune-suppressive environment. It highlights recent advances in therapeutically targeting the brain TME, emphasizing the need for a comprehensive understanding of the complex microenvironmental landscape of brain malignancies to expand therapeutic strategies. The TME of the brain is distinct from other tissues due to its unique composition, including microglia, astrocytes, and neurons, and its physical protection by the BBB. However, the BBB can be compromised in certain brain tumors, allowing immune cell infiltration. The TME of normal brain and early-stage brain tumors is generally immunosuppressive, posing challenges for immune-oncology strategies. Tumor-associated macrophages (TAMs) are the majority of immune cells in brain tumors, with distinct populations including microglia and bone marrow-derived macrophages (BMDMs). TAMs are pro-tumorigenic and accumulate with higher tumor grade. Targeting TAMs, such as through CSF-1R inhibition, can reduce glioma growth and invasion. However, resistance to CSF-1R inhibitors can develop in some cases. Dendritic cells (DCs) are important antigen-presenting cells in the brain, and DC vaccines have shown promise in glioblastoma treatment. Neutrophils also play a role in brain tumors, with their infiltration associated with acquired resistance and higher glioma grade. S100 proteins are linked to secondary dissemination, particularly in breast cancer. Lymphoid cells, including T cells, B cells, and NK cells, are critical in immune responses. T cell activation and re-education within the brain TME are important for anti-tumor immunity. T regulatory cells (Tregs) are immunosuppressive and can be targeted to enhance anti-tumor immune responses. The BBB is a selective barrier that limits therapeutic agents from reaching the brain, but its integrity can be compromised in certain brain tumors. Vascular normalization, an alternative to anti-angiogenic therapies, aims to improve perfusion and drug delivery. However, anti-angiogenic therapies have shown limited success in brain tumors, with some even causing adverse effects. Astrocytes play a role in brain metastases, supporting tumor growth and invasion. Gliosis, the reactive activation of astrocytes, can contribute to tumor progression and resistance to therapy. Neurons may also contribute to tumor initiation and progression by providing mitogenic signals. The brain extracellular matrix (ECM) differs from other organs, with unique components that influence tumor cell niches, angiogenesis, and invasion. Targeting the TME is a promising approach for brain tumor therapy, with various strategies under investigation, including CSF-1R inhibitors, DC vaccinesThe brain tumor microenvironment (TME) is a critical regulator of cancer progression in primary and metastatic brain malignancies. This review discusses the unique features of the brain TME, including brain-resident cell types, the blood-brain barrier (BBB), and the immune-suppressive environment. It highlights recent advances in therapeutically targeting the brain TME, emphasizing the need for a comprehensive understanding of the complex microenvironmental landscape of brain malignancies to expand therapeutic strategies. The TME of the brain is distinct from other tissues due to its unique composition, including microglia, astrocytes, and neurons, and its physical protection by the BBB. However, the BBB can be compromised in certain brain tumors, allowing immune cell infiltration. The TME of normal brain and early-stage brain tumors is generally immunosuppressive, posing challenges for immune-oncology strategies. Tumor-associated macrophages (TAMs) are the majority of immune cells in brain tumors, with distinct populations including microglia and bone marrow-derived macrophages (BMDMs). TAMs are pro-tumorigenic and accumulate with higher tumor grade. Targeting TAMs, such as through CSF-1R inhibition, can reduce glioma growth and invasion. However, resistance to CSF-1R inhibitors can develop in some cases. Dendritic cells (DCs) are important antigen-presenting cells in the brain, and DC vaccines have shown promise in glioblastoma treatment. Neutrophils also play a role in brain tumors, with their infiltration associated with acquired resistance and higher glioma grade. S100 proteins are linked to secondary dissemination, particularly in breast cancer. Lymphoid cells, including T cells, B cells, and NK cells, are critical in immune responses. T cell activation and re-education within the brain TME are important for anti-tumor immunity. T regulatory cells (Tregs) are immunosuppressive and can be targeted to enhance anti-tumor immune responses. The BBB is a selective barrier that limits therapeutic agents from reaching the brain, but its integrity can be compromised in certain brain tumors. Vascular normalization, an alternative to anti-angiogenic therapies, aims to improve perfusion and drug delivery. However, anti-angiogenic therapies have shown limited success in brain tumors, with some even causing adverse effects. Astrocytes play a role in brain metastases, supporting tumor growth and invasion. Gliosis, the reactive activation of astrocytes, can contribute to tumor progression and resistance to therapy. Neurons may also contribute to tumor initiation and progression by providing mitogenic signals. The brain extracellular matrix (ECM) differs from other organs, with unique components that influence tumor cell niches, angiogenesis, and invasion. Targeting the TME is a promising approach for brain tumor therapy, with various strategies under investigation, including CSF-1R inhibitors, DC vaccines