Abstract

Glycans regulate multiple physiological processes, including immune recognition and cancer progression. In disease, altered glycan landscapes are interpreted by human lectins. Functional glycan-lectin interactions are difficult to profile because glycans are not genome-encoded and their changes are poorly captured by existing multimodal methods. We present two platforms, single-cell outlining and transcriptome sequencing (scGOAT-seq) and GlycoScope, which use human lectins to enable functional glycan accessibility into single-cell and spatial multiomic measurements. ScGOAT-seq quantifies lectin-accessible glycan states with gene expression, while GlycoScope enables multiplexed in situ co-detection of glycans and proteins in tissues. Applying these approaches to immune cells, we identify stimulus-specific glycan remodeling and show that distinct Siglec-ligand-defined programs stratify immune activation states not captured by traditional methods; in follicular lymphoma, GlycoScope, resolves spatial glycan programs associated with malignant B cells and localized immune microenvironments. The presented methods provide a general framework for integrating functional glycan accessibility into single-cell and spatial multiomics.