Single-Cell Glycomics of the Pancreatic Tumor Microenvironment: Technologies, Glyco-Immune Checkpoints, and...

In this Review, we summarize recent conceptual and technological advances in single-cell glycomics, with a particular focus on emerging strategies that enable glycan-resolved analysis of tumor-immune interactions. We highlight single-cell glycan and RNA sequencing (scGR-seq), a methodology that converts glycan information into amplifiable nucleic acid signals, enabling simultaneous profiling of transcriptomes and glycomes at the single-cell level. In parallel, we introduce GlycoChat, a computational framework designed to systematically infer and visualize glycan-lectin interaction networks within the TME. Integrative application of these approaches to pancreatic ductal adenocarcinoma (PDAC) reveals extensive glycan remodeling during epithelial-mesenchymal transition (EMT) and demonstrates that basal-like PDAC cells selectively reinforce interactions with lectin receptors expressed on innate immune cells, particularly tumor-associated macrophages. These EMT-driven glycan-lectin circuits are proposed to transmit immunosuppressive signals within the TME and show a strong association with clinical outcomes. Collectively, these advances highlight glycans as active mediators, rather than solely passive tumor markers of immune regulation, and provide a conceptual framework for understanding and potentially exploiting glycan-mediated immune regulation in cancer.