NKG2D upregulation sensitizes tumors to combined anti-PD1 and anti-VEGF therapy and prevents hearing loss.

NKG2D upregulation sensitizes tumors to combined anti-PD1 and anti-VEGF therapy and prevents hearing loss. Nature communications Lu, S., Yin, Z., Wu, L., Sun, Y., Chen, J., Wu, L. M., Oblinger, J. L., Blake, D. C., Xiu, B., Landegger, L. D., Seist, R., Ho, W., Jones, A. P., Muzikansky, A., Stankovic, K. M., Plotkin, S. R., Chang, L. S., Xu, L. 2026; 17 (1): 1148

Abstract

NF2-related schwannomatosis (NF2-SWN) is a debilitating condition, characterized by bilateral vestibular schwannomas (VSs) that progressively cause irreversible sensorineural hearing loss. Current management relies on surgery or radiotherapy, while bevacizumab (aVEGF) is used off-label, with variable and often transient efficacy. Effective therapies that durably suppress tumor growth and preserve hearing are urgently needed. Although immune checkpoint inhibitors have transformed cancer treatment, their efficacy in non-malignant tumors such as VS remains unclear. Here, we evaluate combined anti-PD1 (aPD1) and aVEGF therapy in two syngeneic, immune-competent VS models. Combination treatment significantly outperforms either monotherapy, inhibiting tumor growth and preventing hearing loss. Mechanistically, aVEGF enhances aPD1 efficacy by normalizing tumor vasculature, improving drug delivery and immune cell infiltration, and promoting cytotoxicity of T and NK cells via NKG2D upregulation. Combined treatment effectively controls tumor growth that progresses despite anti-VEGF therapy. These findings support aPD1 and aVEGF combination therapy as a promising strategy for NF2-SWN.

View details for DOI 10.1038/s41467-026-68865-8

View details for PubMedID 41673019

View details for PubMedCentralID PMC12894996