Sanghuang polysaccharides as emerging immunomodulators: linking molecular structure, immune recognition and the gut microbiota–immune axis

Sanghuang — a group of medicinal polypores now taxonomically reassigned from Phellinus linteus sensu lato to the genus Sanghuangporus — has been used for two millennia in East Asian medicine, and its polysaccharides are now recognized as the principal immunologically active constituents. Yet the field remains fragmented: “Sanghuang polysaccharide” is not a single molecule but a structurally heterogeneous family of β-glucans, heterogalactans, mannans and polysaccharide–protein complexes whose immune effects may be governed by the coupling of molecular structure × pattern-recognition receptor × cell type × host microenvironment. This review synthesizes current evidence across five layers — chemical structure, immune recognition, innate and adaptive cellular immunomodulation, immunometabolic regulation and the potential for trained immunity, and the gut microbiota–immune axis — and maps them onto immune-mechanism-based applications spanning tumor immune-microenvironment remodeling, barrier immunity and microbiota-associated regulation, host defense and inflammatory resolution, and immunometabolic disorders. We critically grade the receptor evidence, showing that most Sanghuang studies remain correlative (pathway phosphorylation or cytokine readouts) rather than demonstrating direct receptor engagement, in contrast to the benchmark fungal β-glucans lentinan, schizophyllan and PSK/Krestin, for which Dectin-1, Toll-like receptor and complement receptor 3 mechanisms are established. We further examine oral bioavailability and pharmacokinetic constraints that shape whether luminal, gut-associated lymphoid or systemic mechanisms dominate. We propose a minimum reporting standard (Box 1) covering species authentication, extraction and purity control (including endotoxin and protein/phenolic contamination), structural characterization and receptor validation, and outline a multi-omics- and AI-enabled roadmap to move the field from asking “is it effective?” to “which structure, via which receptor, in which cell and which disease context?”. Sanghuang polysaccharides therefore emerge as context-dependent immunomodulators rather than universal immune stimulants, and they represent a tractable model system for structure-defined fungal immunomodulators — but translation requires rigorous standardization and mechanistic validation.