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

Abstract 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 the two molecular subgroups. Notably, we found significant differences in clinical characteristics and prognostic outcomes across VS subgroups. Furthermore, snRNA-seq revealed cellular heterogeneity within the VS microenvironment, with phenotypic transitions in SCs and immune cells that closely recapitulated the sequential stages of nerve injury and repair. Collectively, our study reveals that SC plasticity and immune cell dynamics within the tumor microenvironment contribute to intertumoral heterogeneity in vestibular schwannomas, offering insights into the biological processes underlying tumor progression and nerve injury-repair programs.