Addition of Losartan to Immune Checkpoint Blockade Improves Tumor Control and Neurological Outcomes in Models of NF2-Related Schwannomatosis

NF2 -related schwannomatosis ( NF2 -SWN) is a devastating genetic disorder characterized by the development of bilateral vestibular schwannomas (VSs), which are histologically benign tumors that cause hearing loss and vestibular dysfunction. Currently, there are no FDA-approved pharmacologic therapies for VS or VS-associated hearing loss, representing a major unmet medical need for patients with NF2 -SWN. Although immunotherapy has transformed the treatment of many solid malignancies, its efficacy in VS has not been comprehensively evaluated. We employed VS mouse models that faithfully recapitulate tumor-induced hearing loss and ataxia to evaluate the therapeutic efficacy of anti-PD-1 (αPD-1) immunotherapy alone and in combination with losartan, an angiotensin II type 1 receptor blocker known to reduce tumor extracellular matrix density and normalize tumor vascular perfusion. Tumor growth, survival, hearing function, and neurological outcomes were assessed. Losartan significantly enhanced the intratumoral delivery of αPD-1 antibody and increased immune effector cell infiltration in VS. Consequently, combined losartan and αPD-1 therapy more effectively inhibited tumor growth and prolonged survival compared with monotherapy. In parallel, losartan attenuated inflammatory signaling, thereby reducing neuro-edema. As a result, the combination treatment more effectively prevented tumor-induced hearing loss and alleviated ataxia in the VS mouse model. Targeting the fibrotic tumor microenvironment with losartan sensitizes vestibular schwannomas to immunotherapy and improves neurological outcomes. These findings provide critical preclinical evidence supporting a novel combination strategy using ICIs for NF2 -SWN and offer important insights for the design of future clinical trials aimed at suppressing VS growth while preserving hearing and neurological function.