Zhao Yu, Zhou Xinying, Hong Lei, Yao Jinyu, Pan Jinlin, Shafi Shaheryar, Siraj Sami, Ahmad Nafees, Liu Jiangang, Zhao Rongchuan, Sun Minxuan
School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230006, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou 215163, China.
Institute of Clinical Medicine Research, Suzhou Hospital, Affiliated Hospital of Medical School, Nanjing University. Suzhou Science and Technology Town Hospital., No. 1 Lijiang Road, Suzhou 215153, China.
Int Immunopharmacol. 2025 Feb 6;147:113915. doi: 10.1016/j.intimp.2024.113915. Epub 2024 Dec 30.
Glioblastoma (GBM) is the most aggressive tumor in the central nervous system. Tumor-associated macrophage (TAMs) represent a major immune cell population in tumor microenvironment (TME) and exert immunosuppressive effects that impede GBM treatment. Morusin is a flavonoid extracted from mulberry trees and has anti-tumor properties against various cancers, including glioma. However, the impact of morusin on the TME of gliomas has not been explored.
We evaluated the effect of morusin on the tumor microenvironment using a mouse glioma model through in vivo and in vitro experiments. In vitro experiments demonstrated the effects of morusin on the viability of RAW264.7 and THP1 cells, and the migration ability of M2 macrophages. Furthermore, we investigated the effect of conditioned medium (CM) of morusin-treated M2 macrophages on the migration of glioblastoma cell lines GL261, U87, and U251.
Morusin alleviated the GBM progression and prolonged mouse survival by inhibiting the ratio of macrophages to CD206 macrophages. Mechanistically, we demonstrated that morusin could effectively inhibit the secretion of the chemokine CCL4 in M2 macrophage which consequently decreased CCL4-dependent CCR5 activation. This leads to the reduced migration of both macrophages and glioblastoma cells in TME. These findings provide a strong rationale for the development of morusin as a potential therapeutic agent for GBM, either as a standalone treatment or in combination with other immunotherapeutic strategies, and warrant further preclinical and clinical investigations.
胶质母细胞瘤（GBM）是中枢神经系统中最具侵袭性的肿瘤。肿瘤相关巨噬细胞（TAM）是肿瘤微环境（TME）中的主要免疫细胞群体，发挥免疫抑制作用，阻碍GBM治疗。桑色素是从桑树中提取的一种黄酮类化合物，对包括胶质瘤在内的多种癌症具有抗肿瘤特性。然而，桑色素对胶质瘤TME的影响尚未得到研究。
我们通过体内和体外实验，使用小鼠胶质瘤模型评估了桑色素对肿瘤微环境的影响。体外实验证明了桑色素对RAW264.7和THP1细胞活力以及M2巨噬细胞迁移能力的影响。此外，我们研究了经桑色素处理的M2巨噬细胞的条件培养基（CM）对胶质母细胞瘤细胞系GL261、U87和U251迁移的影响。
桑色素通过抑制巨噬细胞与CD206巨噬细胞的比例，缓解了GBM进展并延长了小鼠存活时间。从机制上讲，我们证明桑色素可以有效抑制M2巨噬细胞中趋化因子CCL4的分泌，从而降低CCL4依赖的CCR5激活。这导致TME中巨噬细胞和胶质母细胞瘤细胞的迁移减少。这些发现为将桑色素开发为GBM的潜在治疗药物提供了有力依据，无论是作为单一治疗还是与其他免疫治疗策略联合使用，都值得进一步的临床前和临床研究。
