Modern xenotransplantation: rewiring glycan-mediated immunogenicity via genome-glycome convergence

Xenotransplantation addresses global organ shortages but faces species-specific glycan antigen barriers. Dominant xenoantigens (α-Gal, Neu5Gc, Sda) trigger hyperacute rejection via antibody-mediated immune cascades, complement activation, and thromboinflammation. Advances in precision genome editing, particularly CRISPR-Cas9 now facilitate the generation of multi-gene-edited pigs lacking GGTA1/CMAH/B4GALNT2 to eliminate these epitopes, co-expressing human complement/coagulation regulators to prolong graft survival. The systematic discovery of novel xenoantigens and validation of their immunogenicity, however, are still hampered by limited access to well-defined glycans and reliable functional assays. Emerging technologies, including advanced glycomics, glycoproteomics, and AI-driven prediction, are now accelerating the mapping and prioritisation of immunogenic glycan epitopes. This review synthesises three advances: glycan xenoantigens' immunodominant roles, multi-gene porcine models, and glycomics-driven epitope decoding. These discoveries directly inform next-generation genetic edits and clinical immune monitoring. Convergence of glycobiology, genome engineering, and multi-omics accelerates clinical translation, offering a roadmap for developing rejection-free organs.