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Perioperative Management of Targeted and Immunologic Agents in Neurosurgical Oncology. BACKGROUND AND OBJECTIVES: The rapid expansion of oncologic systemic therapy has produced major advances for patients with cancer. This array of pharmacologic mechanisms also presents challenges for neurosurgeons. Many agents impair wound healing, hemostasis, and immune function, elevating perioperative risk. Yet, consolidated evidence-based guidance for neurosurgical drug management remains limited. Our goal is to provide a comprehensive, clinically actionable framework for perioperative management of targeted and biologic therapies in patients undergoing neurosurgical procedures. METHODS: We conducted a systematic review of pivotal clinical trials, US Food and Drug Administration safety data, meta-analyses, and society guidelines to assess the impact of key agents on surgical outcomes. Drug classes were evaluated based on pharmacokinetics, mechanism of action, and adverse events relevant to wound healing, bleeding, and immune dysregulation. Recommendations were stratified by risk level and supported by available evidence and expert consensus. RESULTS: Wound healing risk was highest with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies and mammalian target of rapamycin inhibitors, warranting extended preoperative holds (≥4 weeks for VEGF inhibitors, ≥1 week for mammalian target of rapamycin agents) and postoperative delays of 2 to 4 weeks (fibroblast and angiogenesis suppression). Bleeding risk was most significant with VEGF receptor-tyrosine kinase inhibitors and Bruton's tyrosine kinase inhibitors (eg, ibrutinib), independent of platelet count, necessitating short-term holds of up to 1 week with resumption after 3 to 7 days. Immunosuppression noted with CDK4/6 inhibitors, janus kinase inhibitors, and biologic immunomodulators (eg, TNF, IL-6, CD20 blockers), increasing postoperative infection risk. These agents often require brief interruption (2-7 days) with resumption 1 to 2 weeks postoperative depending on half-life and schedule. For BRAF/MEK inhibitors and immune checkpoint inhibitors, perioperative data are limited. CONCLUSION: Modern systemic therapies necessitate refinement of perioperative management in neurosurgical oncology. This review synthesizes data into a pragmatic framework for drug timing and risk mitigation. Considering interruption intervals is essential to balance surgical safety with oncologic control. Integrating these principles can reduce complications, standardize care, and improve outcomes for this complex patient population.