Glycan-encoded immune checkpoints and allorecognition: a mechanistic framework for transplantation and organ engineering.

Glycans constitute a structurally diverse and immunologically instructive layer that shapes how transplanted tissues are interpreted by the host immune system. Although glycoengineering approaches and glycocalyx-focused strategies have gained momentum, the mechanistic pathways through which immune cells decode glycan information remain underexplored in transplantation biology. This hybrid Perspective integrates selected mechanistic foundations with a broader conceptual framework that positions glycans as upstream immune checkpoints governing graft recognition and early innate-adaptive integration. We synthesize advances across four major axes of glycan-regulated immunity: Siglec (Sialic acid-binding immunoglobulin-type lectin)-mediated inhibitory circuits that calibrate macrophage, neutrophil, and NK-cell activation; C-type lectin receptor pathways that program antigen-presenting cells and govern antigen routing; NK-cell glycan-sensing mechanisms shaped by sialylation density, glycan topology, and ischemia-reperfusion-induced glycocalyx collapse; and complement regulation through Factor H, which interprets sialic acid motifs to restrain alternative pathway amplification. We further examine how these innate pathways intersect with glycan-dependent modulation of direct, indirect, and semi-direct allorecognition, including effects on MHC stability, exosomal transfer, antigen uptake, and T-cell intrinsic glycan checkpoints. Together, these mechanisms reveal that glycans function as a pre-recognition code that precedes and conditions classical protein-centric checkpoints by initiating, amplifying and sustaining the classical pathways, and influencing whether grafts are classified as self-like, stressed, or foreign. By consolidating these pathways into a unified model, this Perspective highlights glycan composition and architecture as a foundational design parameter for next-generation immune-compatible organ modifications and outlines mechanistic priorities for advancing glycan-informed strategies in transplantation.