Biomaterial engineering of the tumor glycocalyx for cancer immunotherapy

The tumor glycocalyx is a dynamic biochemical and physical interface that shapes receptor accessibility, immune cell contact and glycan-lectin signaling. Cancer-associated remodeling, including hypersialylation, truncated O-glycans, altered fucosylation and mucin-rich architectures, promotes immune evasion while creating therapeutically exploitable surface features. Biomaterials offer spatial, temporal and cellular control over these distributed glycan pathways. Nanoparticles, glycopolymers, enzyme conjugates, engineered vesicles, hydrogels and synthetic cell-surface modules can suppress glycan biosynthesis, remove terminal sialic acids, dismantle mucin barriers, install bioorthogonal or antigenic cues and exploit tumor-associated glycoforms for targeting and local assembly. Related platforms can also interrupt CD24-Siglec-10/G, Siglec-15 and galectin-centered checkpoints or reprogram glycan recognition in therapeutic lymphocytes and myeloid cells, thereby enhancing trafficking, phagocytosis, antigen presentation and cytotoxicity. Translation will require control of tumor glycan heterogeneity, on-target, off-tumor activity, glycocalyx access, biodistribution and catalytic duration, together with solutions for species-specific glycan-lectin biology, enzyme immunogenicity, biomarker selection and manufacturing reproducibility. Humanized models, longitudinal glycomics, spatial glycoproteomics and modular, biomarker-guided platforms may enable conditional or reversible remodeling while minimizing unintended remodeling of physiological glycans on healthy tissues during systemic treatment, ultimately converting the tumor glycocalyx from an adaptable mechanism of immune escape into a controllable therapeutic interface.