Spatial—glycomic immune signatures in metabolic dysfunction-associated steatotic liver disease (MASLD) progression 2310277

Abstract

Abstract Introduction Metabolic dysfunction—associated steatotic liver disease (MASLD) progresses from chronic inflammation and fibrosis to hepatocellular carcinoma (HCC). Yet the spatial remodeling of immune-cell N-glycosylation during this transition remains poorly understood. Because glycosylation critically regulates immune cell function, trafficking, and antitumor immune responses, defining how immune glycan landscapes are rewired in situ across MASLD stages is essential for identifying actionable biomarkers and therapeutic targets. Methods We performed imaging mass cytometry (IMC) and MALDI N-glycan imaging on human MASLD liver biopsies spanning multiple fibrosis stages, as well as on end-stage MASLD tissues with and without hepatocellular carcinoma. Multimodal spatial datasets were co-registered and jointly analyzed using our newly developed MIMIC pipeline, enabling pixel-level integration of immune cell phenotypes and N-glycan distributions across tissue compartments. Results IMC revealed a progressive reorganization of immune neighborhoods, shifting from Kupffer cell—T cell interactions in early fibrosis toward T cell—dominated networks in advanced disease. Spatial glycomics uncovered domain-specific glycan organization. Integrated pixel-level analysis identified cell type—associated glycan signatures and demonstrated differences between intratumoral, tumor-adjacent, and healthy glycan features consistent with impaired immune surveillance in MASLD-associated HCC. Conclusion These findings establish immune glycan remodeling as a spatially organized hallmark of MASLD progression and MASLD-HCC. The integrated IMC—glycomics framework provides a practical and scalable approach for biomarker discovery and supports therapeutic targeting of glycosylation pathways in metabolically diseased liver. Funding Source N/A Topic Categories Immune Mechanisms of Human Disease (HUM)