Divergent Schwann cell–immune cell trajectories across vestibular schwannoma subtypes mirror nerve injury-repair programs

Although Schwann cells (SCs) are increasingly recognised as active contributors to cancer progression, their cell-autonomous oncogenic mechanisms underlying vestibular schwannoma (VS) development remain poorly defined. Moreover, the roles of heterogeneity within the tumour microenvironment (TME) in VS pathogenesis remain unclear. In this study, we performed integrative multi-omic analyses of sporadic VSs and NF2-related schwannomatosis (NF2-SWN) VSs, using bulk RNA sequencing, single-nucleus RNA sequencing (snRNA-seq), DNA methylation profiling, and immunohistochemistry (IHC). Transcriptomic and DNA methylation profiling analyses identified two distinct molecular subgroups, immune-enriched schwannoma (IES) and immune-depleted schwannoma (IDS), independent of syndromic status. We developed multigene and IHC-based classifiers that robustly distinguish two molecular subgroups. We identified distinct clinical characteristics and outcomes across four VS subtypes (sporadic IES, sporadic IDS, NF2-SWN IES, and NF2-SWN IDS). snRNA-seq analysis uncovered dynamic cellular heterogeneity within the VS microenvironment across the four VS subtypes. Furthermore, snRNA-seq data revealed dynamic phenotypic transitions in SCs and immune cells that closely recapitulated the sequential stages of nerve injury and repair. Collectively, our study establishes that dysregulated reprogramming of SCs and immune cells within TME is a key driver of VS pathogenesis, providing a mechanistic foundation for therapeutic strategies with the dual potential to control tumour growth and promote nerve regeneration.