Spatially Resolved Multiomics Reveals Metabolic Remodeling and Autophagy Activation in Adamantinomatous Craniopharyngiomas

ABSTRACT Adamantinomatous craniopharyngioma (ACP), a benign yet highly recurrent and therapy—resistant intracranial tumor, remains a considerable clinical challenge because of its complex pathological structure, infiltrative growth, and limited treatment options. Here, integrated spatially resolved multiomics is employed—including single‐cell spatial transcriptomics via CosMx SMI and spatially resolved metabolomics via AFADESI‐MSI, accompanied by bulk metabolomics and functional validation—to unravel the driving factors of ACP progression and recurrence. Analysis results reveal three interdependent biological hallmarks: first, the spatial segregation and molecular heterogeneity of 10 distinct tumor epithelial cell subpopulations within the ACP, each of which presents unique transcriptional signatures; second, in tumor regions and recurrent tumor epithelium tissues, stronger transporter‐mediated choline/ethanolamine uptake from cystic fluid and significant upregulation of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) synthesis is observed, creating the enhanced “cystic fluid–tumor cell” and “choline/ethanolamine–PC/PE” metabolic axis, and demonstrating the spatial metabolic remodeling of ACP; and third, this metabolic axis directly couples to autophagy activation of corresponding regions in ACP tissue, which is validated by multi‐immunohistochemistry for Beclin1 and GABARAP. Together, these findings reveal metabolic remodeling and autophagic activation as critical drivers of ACP progression and recurrence and provide an opportunity for precise biomarker‐driven treatment of this intractable tumor.