School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, People's Republic of China.
State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an Jiaotong University, Xi'an, China.
Phytother Res. 2024 Nov;38(11):5088-5106. doi: 10.1002/ptr.8309. Epub 2024 Aug 9.
Tumor-associated macrophages (TAMs) in non-small cell lung cancer (NSCLC) promote tumor cell metastasis by interacting with cancer cells. Ginsenoside Re is capable of modulating the host immune system and exerts anticancer effects through multiple pathways. Both AMPK and STING are involved in the regulation of MΦ polarization, thereby affecting tumor progression. However, whether there is a regulatory relationship between them and its effect on MΦ polarization and tumor progression is unclear. The aim of this study was to provide mechanistic evidence that ginsenoside Re modulates MΦ phenotype through inhibition of the AMPKα1/STING positive feedback loop and thus exerts an antimetastatic effect in NSCLC immunotherapy. Cell culture models and conditioned media (CM) systems were constructed, and the treated MΦ were analyzed by database analysis, RT-PCR, Western blotting, flow cytometry, and immunofluorescence to determine the regulatory relationship between AMPK and STING and the effects of ginsenoside Re on MΦ polarization and tumor cells migration. The effects of ginsenoside Re (10, 20 mg/kg/day) on TAMs phenotype as well as tumor progression in mice were assessed by HE staining, immunohistochemical staining, and Western blotting. In this study, AMPKα1/STING positive feedback loop in NSCLC TAMs induced M2 type polarization, which in turn promoted NSCLC cell migration. In addition, ginsenoside Re was discovered to inhibit M2-like MΦ polarization, thereby inhibiting NSCLC cell migration. Mechanistically, Re was able to inhibit the formation of the AMPKα1/STING positive feedback loop, thereby inhibiting its induction of M2-like MΦ and consequently inhibiting the epithelial-mesenchymal transition (EMT) process of NSCLC cells. Furthermore, in mouse models, Re was found to suppress LLC tumor growth and colonization by inhibiting M2-type polarization of TAMs. Our finding indicates that ginsenoside Re can effectively modulate MΦ polarization and thus play an important role in antimetastatic immunotherapy of NSCLC.
肿瘤相关巨噬细胞（TAMs）在非小细胞肺癌（NSCLC）中通过与癌细胞相互作用促进肿瘤细胞转移。人参皂苷 Re 能够调节宿主免疫系统，并通过多种途径发挥抗癌作用。AMPK 和 STING 都参与调节 MΦ 极化，从而影响肿瘤进展。然而，它们之间是否存在调节关系及其对 MΦ 极化和肿瘤进展的影响尚不清楚。本研究旨在提供机制证据，表明人参皂苷 Re 通过抑制 AMPKα1/STING 正反馈环调节 MΦ 表型，从而在 NSCLC 免疫治疗中发挥抗转移作用。构建细胞培养模型和条件培养基（CM）系统，通过数据库分析、RT-PCR、Western blot、流式细胞术和免疫荧光分析来分析处理后的 MΦ，以确定 AMPK 和 STING 之间的调节关系以及人参皂苷 Re 对 MΦ 极化和肿瘤细胞迁移的影响。通过 HE 染色、免疫组织化学染色和 Western blot 评估人参皂苷 Re（10、20mg/kg/天）对小鼠 TAMs 表型和肿瘤进展的影响。在本研究中，NSCLC TAMs 中的 AMPKα1/STING 正反馈环诱导 M2 型极化，进而促进 NSCLC 细胞迁移。此外，发现人参皂苷 Re 可抑制 M2 样 MΦ 极化，从而抑制 NSCLC 细胞迁移。从机制上讲，Re 能够抑制 AMPKα1/STING 正反馈环的形成，从而抑制其诱导的 M2 样 MΦ，进而抑制 NSCLC 细胞的上皮间质转化（EMT）过程。此外，在小鼠模型中，Re 通过抑制 TAMs 的 M2 型极化，发现可抑制 LLC 肿瘤的生长和定植。我们的研究结果表明，人参皂苷 Re 可以有效地调节 MΦ 极化，从而在 NSCLC 的抗转移免疫治疗中发挥重要作用。
