A low-molecular-weight glucan from Lycium barbarum reprograms tumor-associated macrophages involving the Dectin-1/NOX2 axis to suppress hepatoma.

Polysaccharides from Lycium barbarum L., particularly LBP3, exhibit immunomodulatory and anti-tumor properties, yet their active constituents remain unclear. Here, LBP3 was fractionated into PolyA, PolyB, and PolyC. PolyC emerged as the key bioactive component, enhancing phagocytosis in vitro and showing superior anti-tumor efficacy to PolyA in vivo (125 mg/kg). Mechanistically, PolyC upregulates gp91 and p47 expression involving Dectin-1, driving M2 macrophages toward an M1 phenotype and enhancing antigen presentation and adaptive immunity. Purification of PolyC yielded its major subfraction, PolyD, which was structurally characterized as a predominant α-(1 → 4)-linked glucan with α-(1 → 6)-branching and a terminal β-linkage. Despite its α-configuration, PolyD retains Dectin-1 agonistic activity, suggesting that Dectin-1 may recognize specific α-glucan conformations. In summary, this study establishes PolyC as the key bioactive component of LBP3 and PolyD as its structurally defined α-glucan, demonstrating that PolyC's anti-tumor activity involves Dectin-1-mediated NOX2 upregulation in TAMs, expanding the chemical diversity of Dectin-1 agonists and informing immunotherapy design.