Macrophages are the most abundant cells in tumor stroma and their polarization within tumor microenvironment exert the key roles in tumorigenesis. Astragaloside IV is a natural extract from traditional Chinese herbal Radix Astragali, and fulfills pleiotropic function in several cancers. Nevertheless, its function in ovarian cancer microenvironment remains elusive. In the present research, astragaloside IV exhibited little cytotoxicity within a certain dose range in THP-1 cells. Moreover, astragaloside IV suppressed the ratio of CD14⁺CD206⁺ cells in IL-4/IL-13-treated THP-1 macrophages and transcripts of M2 macrophage markers (including CD206, CCL24, PPARγ, Arg-1, IL-10), indicating the inhibitory effects of astragaloside IV on IL-4/IL-13-induced macrophage M2 polarization. Intriguingly, astragaloside IV antagonized M2 macrophages coculture-evoked cell proliferation, invasion and migration in ovarian cancer cells. During this process, administration with astragaloside IV restrained the high expression of high-mobility group box1 (HMGB1) and TLR4 in macrophages co-cultured with ovarian cancer cells, concomitant with decreases in release of M2 marker TGF-β, MMP-9 and IL-10. Moreover, targeting the HMGB1 signaling reversed M2 macrophages-induced ovarian cancer cell proliferation, invasion and migration. Noticeably, exogenous HMGB1 overturned the inhibitory efficacy of astragaloside IV against macrophage M2 polarization-evoked malignant potential in ovarian cancer cells. Together, these findings suggest that astragaloside IV may protect against M2 macrophages-evoked malignancy in ovarian cancer cells by suppressing the HMGB1-TLR4 signaling. Therefore, astragaloside may alleviate the progression of ovarian cancer by regulating macrophage M2 polarization within tumor microenvironment, implying a promising therapeutic strategy against ovarian cancer.

巨噬细胞是肿瘤基质中最丰富的细胞，它们在肿瘤微环境中的极化在肿瘤发生中起关键作用。黄芪甲苷IV是传统中草药黄芪的天然提取物，在多种癌症中具有多效性。然而，其在卵巢癌微环境中的功能仍然难以捉摸。在本研究中，黄芪甲苷IV在THP-1细胞中在一定剂量范围内几乎没有细胞毒性。此外，黄芪甲苷IV抑制了CD14 ⁺ CD206 ⁺的比例IL-4 / IL-13处理的THP-1巨噬细胞中的细胞和M2巨噬细胞标志物的转录本（包括CD206，CCL24，PPARγ，Arg-1，IL-10），表明黄芪甲苷IV对IL-4 /具有抑制作用IL-13诱导巨噬细胞M2极化。有趣的是，黄芪甲苷IV拮抗M2巨噬细胞共同培养引起卵巢癌细胞的细胞增殖，侵袭和迁移。在此过程中，黄芪甲苷IV的给药抑制了高流动性基团box1（HMGB1）和TLR4在与卵巢癌细胞共培养的巨噬细胞中的高表达，同时降低了M2标志物TGF-β，MMP-9和IL的释放-10。此外，靶向HMGB1信号逆转了M2巨噬细胞诱导的卵巢癌细胞的增殖，侵袭和迁移。明显地，外源HMGB1推翻了黄芪甲苷IV对卵巢癌细胞中巨噬细胞M2极化诱发的恶性潜能的抑制作用。在一起，这些发现表明，黄芪甲苷IV可以通过抑制HMGB1-TLR4信号传导来预防卵巢癌细胞中M2巨噬细胞诱发的恶性肿瘤。因此，黄芪甲苷可通过在肿瘤微环境中调节巨噬细胞M2极化来减轻卵巢癌的进展，这意味着针对卵巢癌的一种有希望的治疗策略。