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Yongjia Yang,1,2 Yujie Zhang,1,2 Xiaoyan Feng,2 Fen Gao,3 Yanhua Ma,1,2 Shaojun Yang1,4 1Key Laboratory of Dunhuang Medicine, Ministry of Education, Gansu University of Chinese Medicine, Lanzhou, Gansu, People’s Republic of China; 2The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, Gansu, People’s Republic of China; 3Clinical Medical College, Hubei College of Chinese Medicine, Jingzhou, Hubei, People’s Republic of China; 4Beihai Hospital of Traditional Chinese Medicine, Beihai, Guangxi, People’s Republic of ChinaCorrespondence: Yanhua Ma, Email 617747928@qq.com Shaojun Yang, Email 3900316815@qq.comBackground: 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. Pleione bulbocodioides 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.Keywords: Pleione bulbocodioides polysaccharides, macrophage polarization, JAK2/STAT3 signaling, hepatocellular carcinoma, tumor immune microenvironment