Immunotherapy in central nervous system tumors

Immunotherapy, defined as strategies that enhance host antitumor immunity by activating innate and adaptive immune responses, has demonstrated remarkable efficacy in hematologic malignancies. However, its application in solid tumors, particularly those affecting the central nervous system (CNS) such as gliomas, brain metastases, primary CNS lymphoma (PCNSL), and medulloblastomas, has been considerably slower. Major barriers to immunotherapy in these contexts include the physical and functional constraints imposed by the blood-brain barrier (BBB), tumor immune evasion, immunosuppressive microenvironments, tumor heterogeneity, and therapeutic resistance. Emerging consensus challenges the traditional notion of CNS immune privilege, recognizing that distinct anatomical sites within the CNS-including the brain parenchyma, meninges, choroid plexus, perivascular spaces, and calvarial bone marrow-exert diverse immunological functions that modulate local and systemic immunity. This review comprehensively summarizes the immune landscape of different CNS compartments and its impact on immunotherapeutic efficacy, delves into the mechanisms of immune evasion and suppression in CNS, reviews the clinical trials conducted on immunotherapy for CNS tumors, meticulously analyzes the factors contributing to the variability in the efficacy of different immunotherapy modalities across various CNS tumors, critically evaluates current challenges in CNS tumor immunotherapy, and highlights innovative strategies including genomics- and immune profiling-guided personalized immunotherapies, combination regimens integrating immunomodulation with conventional treatments, and novel delivery approaches to overcome the BBB. Our aim is to provide an integrated theoretical framework and forward-looking perspectives to facilitate translational advances and optimize precision immunotherapy for CNS tumors.