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

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.