From structural code to immunomodulation: the structure-activity relationship, molecular mechanisms, and...

Chinese yam (Dioscorea opposita Thunb), a traditional medicinal and edible plant, has attracted significant attention for its bioactive components. Chinese yam polysaccharides (CYPs) are regarded as the principal bioactive fraction responsible for its pleiotropic effects, notably immunomodulation. This review systematically summarizes recent advances in understanding the chemical structure, immunomodulatory mechanisms, and structure-activity relationships of CYPs. A core emphasis is placed on the intimate correlation between immunologic activity and specific structural determinants, including molecular weight, monosaccharide profile, glycosidic linkages, and higher-order conformation. Mechanistic studies demonstrate that CYPs are recognized by pattern recognition receptors, primarily TLR4, on the surface of immune cells such as macrophages. This recognition activates pivotal downstream signaling pathways, including NF-κB and MAPK. The subsequent orchestration of cytokine networks enables a homeostatic regulation of both innate and adaptive immunity, characterized by context-dependent immunostimulation and anti-inflammatory potential. Chemical modifications like sulfation and selenylation, alongside bioprocessing strategies such as physical, enzymatic, and fermentation treatments, significantly enhance their immunomodulatory potency. However, clinical translation faces significant hurdles, including incomplete structure-activity understanding, undefined pharmacokinetics, low oral bioavailability, challenges in quality control, and a paucity of systematic clinical safety and efficacy data. This review provides a comprehensive synthesis to inform future research and support the potential development of CYPs as novel immunomodulatory agents.