Mechanistic and translational perspectives on the regulation of macrophage functional states by astragalus polysaccharides

Abstract: Macrophage functional states are increasingly viewed as a dynamic spectrum rather than a fixed M1/M2 dichotomy. Astragalus polysaccharides (APS) are structurally heterogeneous natural polysaccharides with reported immunomodulatory, anti-inflammatory, antioxidant, antitumor and tissue-repair activities; however, their structure-activity relationships, receptor-recognition mechanisms and translational readiness remain incompletely defined. This review summarizes mechanistic and translational evidence for APS-mediated regulation of macrophage functional states, with emphasis on structural heterogeneity, innate immune recognition, pathway crosstalk, disease-context dependence and current barriers to clinical development. A narrative literature review was conducted using PubMed, Web of Science, Scopus, Google Scholar and selected publisher databases. The literature search focused on studies published between 2020 and 2026, with priority given to recent mechanistic, preclinical and translational studies addressing APS, macrophage activation, macrophage polarization, immunometabolism, oxidative stress and disease-specific immune remodeling. Predominantly preclinical evidence suggests that APS do not act as simple unidirectional inducers of M1- or M2-like polarization. Instead, APS appear to modulate macrophage functional states according to structural features, receptor engagement and disease context. TLR4/MyD88/NF-kappaB, MAPK, Notch, PI3K/Akt/Nrf2/HO-1, JAK/STAT, cGAS-STING, NLRP3 inflammasome and immunometabolic pathways form interconnected regulatory networks. Preclinical studies suggest that APS may promote antitumor inflammatory and antigen-presenting programs in tumors while attenuating excessive inflammatory activation and supporting reparative programs in diabetic vascular injury, acute kidney injury and chronic wounds. This review integrates APS structure-activity relationships with macrophage plasticity and translational limitations. Further progress toward clinical development would depend on high-purity fractionation, rigorous quality control, glycomics-based receptor mapping, single-cell and spatial validation, pharmacokinetic and safety studies and well-designed clinical investigations.