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Understanding the process of algorithmic interpretation is essential for safe application in clinical routine. This is paradigmatically true for the most common primary intracranial tumor in adults, meningioma. Here, by applying multiomic profiling and multiple lines of orthogonal computational evaluation in multiple independent datasets, we found that not only tumor cell characteristics but also incremental changes in the tumor microenvironment (TME) have impact on epigenetic meningioma classification and clinical outcome. Besides revealing the decisive role of non-neoplastic cells in the CNS methylation classifier, this challenges the model of distinct meningioma subgroups toward a TME-determined risk continuum. This refines current controversies in molecular meningioma subtyping. In addition, we apply these learnings to devise and validate a simple diagnostic approach for increased clinical prediction accuracy based on immunohistochemistry, which is also applicable in resource-limited settings.<\/jats:p>","DOI":"10.1038\/s41588-025-02475-w","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T10:02:53Z","timestamp":1770631373000},"page":"341-354","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["A microenvironment-determined risk continuum refines subtyping in meningioma and reveals determinants of machine learning-based tumor classification"],"prefix":"10.1038","volume":"58","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8745-4405","authenticated-orcid":false,"given":"Sybren L. 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Schrimp, A.V.D., S.M.P., D.T.W.J. and F.S. are co-founders and shareholders of Heidelberg Epignostix. M.S. became a full-time employee of Heidelberg Epignostix in July 2024, and D.S. became a part-time employee in November 2024. A.P. is a full-time employee of Heidelberg Epignostix since December 2024. M.S., A.V.D., D.T.W.J., V.H. and S.M.P. report patent EP16710700.2. M.S., A.V.D., D.T.W.J., D. Schrimpf, F.S., V.H. and S.M.P. report patent EP4384959A2. E.S.Z. has provided consulting services to Adela. S.L.N.M. and E.M.B. have received speaking fees from Servier. M.C.N. has received a research grant from Novocure, honoraria for consulting and lectures from WISE, MSD, Servier and Osteopore. T.M. is an Advisory Board member of Ipsen Pharma and has received research grants from Biomed Valley Discoveries and Day One Biopharmaceuticals. S.K. is a consultant for and shareholder of Need (San Francisco, CA) and consultant for Brainlab (Munich, Germany) and Ulrich Medical (Ulm, Germany). R.G. reports consultation and a travel grant from Novocure. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}