Advances in Glycyrrhiza polysaccharides: structure-activity relationship, immunomodulatory mechanisms, and...

Immune dysregulation critically drives the pathogenesis of inflammation, malignancy, metabolic disorders, and autoimmunity, creating an urgent demand for safe, efficacious immunomodulatory interventions. Glycyrrhiza polysaccharides (GPs), bioactive macromolecules derived from licorice (Glycyrrhiza spp.), represent promising natural immunomodulators, although their structural determinants and mechanistic bases remain incompletely characterized. This review critical summarizes recent progress in GPs research regarding its structural characteristics, structure-activity relationships, immunomodulatory mechanisms, and translational potential. Relevant literature published between 1990 and 2026 was retrieved from multiple authoritative databases, including PubMed, Web of Science, ScienceDirect, Springer, and Google Scholar. We comprehensively outline how key structural properties including molecular weight, monosaccharide composition, glycosidic linkage patterns, branching architecture, chemical modification, and higher-order conformation are associated with, and may mechanistically contribute to GPs bioactivity, while strictly discriminating validated experimental findings from unconfirmed mechanistic hypotheses. We highlight that variable purity of conventional GPs preparations frequently confounds immunological results, emphasizing the necessity of rigorous endotoxin detection and proteinase digestion to verify polysaccharide-specific effects and exclude impurity-mediated interference. This review further dissects GP regulatory actions on innate and adaptive immune cells, including macrophages, dendritic cells, natural killer cells, T cells, and B cells, with particular attention to the microbiota-gut-immune axis. We also critically evaluate the preclinical potential of GPs as immunotherapeutic candidates, vaccine adjuvants, nutraceuticals, and agricultural additives, while explicitly distinguishing robust preclinical evidence from scarce clinical data. Current GPs immunomodulatory evidence is predominantly obtained from in vitro and animal models, with limited human studies and randomized controlled trials, restricting translational advancement. Collectively, this review highlights the importance of elucidating GPs structure-function principles, provides a refined framework for the standardized development, rational design and clinical translation of GPs-based biologics, and confirms that relevant evidence remains largely preclinical.