Anti-tumor effects of cold atmospheric pressure plasma on vestibular schwannoma demonstrate its feasibility as an intra-operative adjuvant treatment

Vestibular schwannoma (VS), although a benign intracranial tumor, causes morbidities by brainstem compression. Since chemotherapy is not very effective in most Nf2-negative schwannomas, surgical removal or radiation therapy is required. However, depending on the size and site of the tumor, these approaches may cause loss of auditory or vestibular functions, and severely decrease the post-surgical wellbeing. Here, we examined the feasibility of cold atmospheric pressure plasma (CAP) as an intra-operative adjuvant treatment for VS after surgery. Cell death was efficiently induced in both human HEI-193 and mouse SC4 VS cell lines upon exposure to CAP for seven minutes. Interestingly, both apoptosis and necroptosis were simultaneously induced by CAP treatment, and cell death was not completely inhibited by pan-caspase and receptor-interacting serine/threonine-protein kinase 1 (RIK1) inhibitors. Upon CAP exposure, cell death phenotype was similarly observed in patient-derived primary VS cells and tumor mass. In addition, CAP exposure after the surgical removal of primary tumor efficiently inhibited tumor recurrence in SC4-grafted mouse models. Collectively, these results strongly suggest that CAP should be developed as an efficient adjuvant treatment for VS after surgery to eliminate the possible remnant tumor cells, and to minimize the surgical area in the brain for post-surgical wellbeing.