Novel Human Meningioma Organoids Recapitulate the Aggressiveness of the Initiating Cell Subpopulations Identified by ScRNA‐Seq

High‐grade meningioma has an unsatisfactory outcome despite surgery and postoperative radiotherapy; however, the factors driving its malignancy and recurrence remain largely unknown, which limits the development of systemic treatments. Single‐cell RNA sequencing (scRNA‐Seq) technology is a powerful tool for studying intratumoral cellular heterogeneity and revealing the roles of various cell types in oncogenesis. In this study, scRNA‐Seq is used to identify a unique initiating cell subpopulation (SULT1E1(+)) in high‐grade meningiomas. This subpopulation modulates the polarization of M2‐type macrophages and promotes meningioma progression and recurrence. A novel patient‐derived meningioma organoid (MO) model is established to characterize this unique subpopulation. The resulting MOs fully retain the aggressiveness of SULT1E1(+) and exhibit invasiveness in the brain after orthotopic transplantation. By targeting SULT1E1(+) in MOs, the synthetic compound SRT1720 is identified as a potential agent for systemic treatment and radiation sensitization. These findings shed light on the mechanism underlying the malignancy of high‐grade meningiomas and provide a novel therapeutic target for refractory high‐grade meningioma.