Polysaccharides Reprogram Tumor-Associated Macrophages via JAK2/STAT3 Inhibition to Suppress Hepatocellular Carcinoma.

[BACKGROUND] Tumor-associated macrophages (TAMs) are key regulators of the immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC). Sustained activation of the JAK2/STAT3 signaling pathway is closely associated with the maintenance of the pro-tumorigenic M2 macrophage phenotype. polysaccharides (PBPs) have been reported to exhibit immunomodulatory and antitumor activities; however, whether PBPs regulate TAM polarization in HCC and the involvement of JAK2/STAT3 signaling remain unclear.

[METHODS] The monosaccharide composition and molecular-weight distribution of PBPs were first characterized. Their immunomodulatory effects were evaluated in vitro using IL-4/IL-13-induced M2-polarized RAW264.7 macrophages. In vivo, a Hepa1-6 tumor-bearing mouse model was established to assess the effects of PBPs on tumor growth, intratumoral macrophage composition, and JAK2/STAT3 signaling. The JAK2/STAT3 inhibitor AG490 was included as a pharmacological reference.

[RESULTS] PBPs were identified as high-molecular-weight polysaccharides predominantly composed of mannose and glucose and exhibited no cytotoxicity toward macrophages within the tested concentration range. In vitro, PBPs attenuated M2-associated marker expression and reduced the secretion of immunosuppressive cytokines, including interleukin-10 and transforming growth factor-β. In Hepa1-6 tumor-bearing mice, PBPs dose-dependently suppressed tumor growth and remodeled intratumoral macrophage composition, characterized by a decrease in M2 macrophages and a concomitant increase in M1 macrophages. These effects were accompanied by suppressed JAK2/STAT3 signaling and coordinated regulation of apoptosis- and angiogenesis-related factors.

[CONCLUSION] PBPs suppress HCC progression in association with modulation of TAM polarization and inhibition of JAK2/STAT3 signaling. These findings provide mechanistic insight into the immunomodulatory actions of PBPs and support their further investigation as macrophage-targeting agents for HCC.