Mechanism‑targeted therapies for vestibular schwannoma: Emerging molecular pathways and translational horizons

Vestibular schwannoma represents a significant clinical challenge characterized by hearing loss, vestibular dysfunction, and cranial nerve morbidity. Despite advancements in surgery and radiotherapy, pharmacological options for recurrent, bilateral, or progressive disease remain limited. This review synthesizes current evidence on the molecular landscape of vestibular schwannoma, focusing on NF2 and Merlin inactivation as the upstream driver. We highlight how Merlin loss dysregulates interconnected signaling networks, specifically ErbB, PI3K Akt mTOR, MAPK, Hippo YAP TAZ, Wnt beta catenin, and NF kappaB. Furthermore, we examine how the tumor microenvironment, including tumor-associated macrophages, cancer associated fibroblasts, angiogenic mediators, and immune checkpoints, facilitates therapeutic resistance and immune evasion. The manuscript discusses the translational potential of diverse targeted inhibitors, including ErbB agents, mTOR inhibitors, and novel RNA based therapies such as circ 0001665. While bevacizumab remains the most clinically validated strategy for NF2related schwannomatosis (NF2-SWN), clinical responses are heterogeneous and durable efficacy is often elusive. We identify critical translational gaps, including the lack of predictive biomarkers and the limitations of current preclinical models in capturing the tumor microenvironment and tumor-induced hearing loss. Finally, we propose a precision medicine framework necessitating biomarker guided patient stratification, rational combination therapies targeting both intrinsic signaling and the microenvironment, and clinical trials that prioritize functional outcomes such as hearing preservation over radiographic response alone. This review provides a conceptual roadmap for transitioning toward mechanism guided treatment of vestibular schwannoma.