Molecular and genetic insights into vestibular schwannoma.

[BACKGROUND] Vestibular Schwannomas (VS) are benign nerve sheath tumors arising from Schwann cells of the vestibulocochlear nerve, occurring sporadically or in association with neurofibromatosis type 2 (NF2). Clinical management of VS is challenging due to the tumor's location adjacent to critical neural and vascular structures. The primary morbidities are hearing loss and facial nerve dysfunction, which significantly affect quality of life. There are no FDA-approved medical therapies, and treatment typically consists of surgery or radiation, with treatment decisions centered on optimizing hearing and facial nerve preservation.

[METHODS] This review synthesizes recent advances in the molecular characterization of VS.

[RESULTS] The loss of NF2 function, leading to Merlin inactivation, is a key driver of VS tumorigenesis, disrupting multiple growth and survival pathways. Beyond NF2 inactivation, emerging genomic studies have revealed additional molecular alterations, including chromatin remodeling defects and oncogenic gene fusions, broadening our understanding of VS heterogeneity. Recent single-cell and multi-omic studies have uncovered distinct tumor subtypes and highlighted the role of the tumor microenvironment, particularly the interaction between Schwann cells and tumor-associated macrophages (TAMs).

[CONCLUSIONS] These findings have important implications for therapeutic development, as they suggest differential treatment strategies based on molecular and immune profiles. While surgery and radiotherapy remain the standard of care, targeted therapies such as kinase inhibitors, anti-angiogenic agents, and immunotherapies are being investigated to improve patient outcomes.