A cochlea-sparing strategy for non-invasive control of intracranial schwannomas via peripheral irradiation and anti-PD-1 therapy enhanced by STING activation

<b>Rationale:</b> <i>NF2</i>-related schwannomatosis (<i>NF2</i>-SWN) is a progressive neurological disorder with a hallmark of bilateral vestibular schwannomas (VSs), leading to irreversible hearing loss and reduced quality of life. To date, the FDA has not approved any pharmacological therapies for treating VS or hearing loss. While radiotherapy (RT) is the standard treatment for growing VSs, it often exacerbates hearing loss. Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their efficacy in non-malignant tumors like VS remains largely unexamined. <b>Methods:</b> We used immune-competent VS mouse models to assess the efficacy of combined anti-PD1 (αPD1) and RT treatment, tumor growth, and hearing preservation. <b>Results:</b> We found three significant therapeutic benefits: i) RT induces immunogenic cell death and activates the STING pathway, enhancing αPD1 efficacy and generating long-term immune memory, ii) The combination strategy reduces the required RT dose necessary for effective tumor control, potentially minimizing RT injury to surrounding normal tissues, and iii) RT to peripheral nerve tumor induces a systemic abscopal effect, which enhances αPD-1 efficacy to effectively control intracranial schwannomas without direct irradiation, sparing the cochlea from radiation exposure and avoiding auditory radiation injury. <b>Conclusion:</b> Our findings provide a compelling rationale for deploying ICIs in combination with radiotherapy as a novel treatment approach for patients with VS and <i>NF2</i>-SWN.