Small Extracellular Vesicles Derived from NF2-Associated Schwannoma Cells Modulate Tumor Progression and Immunity via HSP90

In-depth exploration of tumor immune suppression mechanisms may provide new therapeutic options for NF2-associated tumors. In this study, we found that sEVs secreted by NF2-associated schwannomas (NF2-EVs) facilitate the conversion of CD14⁺ monocytes into an MDSC-like phenotype, showcasing MDSC-like inhibitory functions. Moreover, these NF2-EVs are capable of enhancing tumor cell proliferation. Through proteomic analysis and subsequent validation of the NF2-EVs, we identified elevated levels of HSP90. When we knocked down HSP90 expression in tumor cells, the sEVs secreted showed diminished capacity to convert monocytes into MDSCs and a reduced ability to promote tumor cell proliferation. Conversely, sEVs secreted by tumor cells that overexpress HSP90 displayed the opposite effects. Further mechanistic studies revealed that HSP90 could influence the expression of AKT/p-AKT and ERK/p-ERK. Our results suggest that NF2 tumor cells could regulate the AKT/p-AKT and ERK/p-ERK pathways to promote tumor cell proliferation and the formation of an immunosuppressive microenvironment by secreting sEVs' HSP90, offering valuable insights into the involvement of HSP90 in exosome-mediated communication within the context of NF2-related schwannomatosis (NF2-SWN). This information has the potential to inform the design of effective immunotherapeutic protocols and offer new treatment options for NF2-SWN patients.