Astragaloside IV in hepatocellular carcinoma: repolarizing macrophages to reprogram the tumor microenvironment.

The establishment of an immunosuppressive tumor microenvironment (TME) represents a central mechanism underlying the failure of conventional therapies and resistance to immunotherapy in hepatocellular carcinoma (HCC). Tumor-associated macrophages (TAMs), as the most abundant immune cell population within this microenvironment, play a pivotal role in establishing immunosuppression, promoting angiogenesis, and driving therapeutic resistance through their polarization toward the M2 phenotype. Astragaloside IV (AS-IV), the principal bioactive constituent of the traditional Chinese medicine Astragalus membranaceus, has recently been recognized for its remarkable immunomodulatory properties. This review systematically summarizes recent advances in understanding the multi-dimensional mechanisms through which AS-IV modulates M2 macrophage polarization. At the signaling pathway level, AS-IV undermines the molecular basis of macrophage polarization by inhibiting signal transducer and activator of transcription 3/6 (STAT3/STAT6) phosphorylation and modulating phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) and AMP-activated protein kinase (AMPK) signaling cascades. At the metabolic level, it influences the metabolic reprogramming of macrophages, thereby altering their functional phenotypes. At the epigenetic level, it may interfere with processes such as histone modifications, thereby attenuating the "memory" of M2 polarization. This multi-layered regulation promotes the reprogramming of TAMs from a pro-tumorigenic M2 phenotype toward an anti-tumor M1-like phenotype, thereby systematically remodeling the HCC immune microenvironment-restoring effector T cell function, reducing immunosuppressive cell infiltration, inhibiting angiogenesis, and ameliorating the fibrotic barrier. This review aims to provide a systematic framework for understanding the immunomodulatory mechanisms of AS-IV and offer a theoretical foundation for the development of novel natural product-based immunotherapeutic strategies for HCC.