Glycan-mediated modulation of cancer metastasis: Mechanisms and therapeutic opportunities

The post-translational modifications, particularly the glycosylation process and complex carbohydrates such as glycans, are covalently attached to the protein plays crucial roles in cellular communication, adhesion, and signaling. Altered glycosylation has emerged as a hallmark of cancer, driving tumor progression, metastasis, immune evasion, and therapy resistance. Aberrant N- and O-glycans, glycolipids, and proteoglycans modulate epithelial-mesenchymal transition, angiogenesis, and immune suppression through complex interactions with glycan-binding proteins like selectins, galectins, siglecs, and lectins. These interactions activate oncogenic signaling, with PI3K/AKT, MAPK/ERK, NF-κB, TGF-β, and Wnt/β-catenin pathways, thereby promoting metastatic colonization and cancer cell survival. Cancer-cell specific glycosylation alterations, such as tumour-associated carbohydrate antigens (TACAs), are increased sialylation and fucosylation, which are evident in several cancers and serve as potential biomarkers and therapeutic targets. Current advances in glycoengineering, CRISPR-based modulation of glycosyltransferases, and antibody–lectin chimaeras have accelerated the development of glycan-targeted therapies. Also, Immunotherapeutic approaches like monoclonal antibodies against GD2, glycan-based vaccines, and CAR-T cells directed at Tn-MUC1 are under clinical trials. Despite challenges posed by glycan heterogeneity and structural complexity, recent advancements in analytical and gene-editing technologies have enhanced precision in characterizing and manipulating the cancer cell glycome. Therefore, the convergence of glycobiology with immuno-oncology has the potential to uncover novel therapeutic avenues, enabling multimodal interventions that integrate glycan-targeting with immune checkpoint blockade or chemotherapeutics. Overall, decoding the glycans glycocode represents a transformative frontier for understanding and controlling cancer metastasis through innovative diagnostic and therapeutic strategies, which are comprehensively discussed in this review.