Immunotherapy in Metastatic Brain Tumors: Mechanisms, Challenges, and Opportunities for Neurosurgical Integration: A...

Brain metastases are the most common intracranial malignancy in adults and represent a major source of neurologic morbidity despite advances in surgery and radiotherapy. Immune checkpoint inhibitors (ICIs) have transformed systemic cancer therapy and are increasingly demonstrating intracranial activity, challenging the long-standing view of the central nervous system as an immune-privileged site.

This narrative review synthesizes mechanistic, translational, and clinical evidence from the past decade examining immunotherapeutic strategies for metastatic brain tumors. We review the neuroimmune microenvironment of brain metastases, including blood-brain and blood-tumor barrier remodeling, myeloid and lymphoid immune niches, and factors that modulate intracranial immune responses. Clinical data supporting the use of ICIs, combination strategies with stereotactic radiosurgery and anti-angiogenic agents, and emerging cellular, viral, and locoregional immunotherapies are discussed, with attention to patterns of intracranial response, resistance, and toxicity. We further examine key challenges unique to the CNS, including corticosteroid-associated immunosuppression and immune-related imaging ambiguity. Throughout, we emphasize the expanding role of neurosurgeons in precision neuro-immuno-oncology through tissue-based discovery, perioperative treatment coordination, steroid-sparing strategies, and development of locoregional delivery platforms.

Immunotherapy has meaningful intracranial activity in selected patients with brain metastases but remains constrained by CNS-specific biological and clinical barriers. Integrating immunotherapy into neurosurgically centered, tissue-driven care pathways are essential for advancing precision treatment and improving neurologic outcomes.