Liensinine reshapes the immune microenvironment and enhances immunotherapy by reprogramming metabolism through the AMPK-HIF-1α axis in hepatocellular carcinoma.

IF 12.8 1区 医学 Q1 ONCOLOGY
Jiahao Liu, Xuan Zhang, Xiaofei Fan, Peng Liu, Ze Mi, Hongpei Tan, Pengfei Rong
{"title":"Liensinine reshapes the immune microenvironment and enhances immunotherapy by reprogramming metabolism through the AMPK-HIF-1α axis in hepatocellular carcinoma.","authors":"Jiahao Liu, Xuan Zhang, Xiaofei Fan, Peng Liu, Ze Mi, Hongpei Tan, Pengfei Rong","doi":"10.1186/s13046-025-03477-6","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with limited treatment options in advanced stages. Liensinine, a natural alkaloid derived from Nelumbo nucifera, has shown promise as an anticancer agent. However, its underlying mechanisms, particularly in modulating tumor metabolism and immune responses, remain poorly understood. This study aimed to investigate the antitumor effects of Liensinine in HCC, focusing on its ability to modulate metabolic pathways, immune responses, and the tumor microenvironment.</p><p><strong>Methods: </strong>HCC cell lines (HUH7 and Hep1-6) were treated with Liensinine in vitro to assess cell viability, migration, proliferation, and apoptosis. Metabolic reprogramming was analyzed through RNA sequencing, Seahorse metabolic assays, and glucose/lactate measurements. The effects on immune cells were studied by treating THP-1 macrophages and peripheral blood mononuclear cells (PBMCs) with conditioned media from Liensinine-treated cells. In vivo, subcutaneous xenograft and orthotopic liver cancer models were used to evaluate the therapeutic efficacy of Liensinine combination with radiotherapy and immunotherapy.</p><p><strong>Results: </strong>Liensinine inhibited HCC cell viability, migration, and proliferation, promoting apoptosis and shifting metabolism from glycolysis to oxidative phosphorylation. This metabolic reprogramming was linked to the activation of the AMPK-HIF-1α axis and increased ROS production. Furthermore, Liensinine induced Endoplasmic reticulum (ER) stress, as evidenced by elevated levels of CHOP and ATF4, which contributed to AMPK activation and suppression of HIF-1α. Liensinine reduced PD-L1 expression, enhanced M1 macrophage polarization, and promoted CD8 + T cell infiltration into tumors. In vivo, Liensinine significantly suppressed tumor growth, reduced vascular density, and reshaped the immune microenvironment by promoting M1 macrophage polarization. Combination therapy with Liensinine, radiotherapy, and immunotherapy resulted in synergistic effects, including enhanced tumor cell apoptosis, increased immune cell infiltration, and improved therapeutic efficacy.</p><p><strong>Conclusion: </strong>Liensinine exerts potent antitumor effects in HCC by reprogramming tumor metabolism, inducing ER stress, enhancing immune responses, and modulating the TME. The combination of Liensinine with immunotherapy and radiotherapy significantly improves therapeutic efficacy, suggesting its potential as a novel treatment strategy for HCC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"208"},"PeriodicalIF":12.8000,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261578/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental & Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13046-025-03477-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with limited treatment options in advanced stages. Liensinine, a natural alkaloid derived from Nelumbo nucifera, has shown promise as an anticancer agent. However, its underlying mechanisms, particularly in modulating tumor metabolism and immune responses, remain poorly understood. This study aimed to investigate the antitumor effects of Liensinine in HCC, focusing on its ability to modulate metabolic pathways, immune responses, and the tumor microenvironment.

Methods: HCC cell lines (HUH7 and Hep1-6) were treated with Liensinine in vitro to assess cell viability, migration, proliferation, and apoptosis. Metabolic reprogramming was analyzed through RNA sequencing, Seahorse metabolic assays, and glucose/lactate measurements. The effects on immune cells were studied by treating THP-1 macrophages and peripheral blood mononuclear cells (PBMCs) with conditioned media from Liensinine-treated cells. In vivo, subcutaneous xenograft and orthotopic liver cancer models were used to evaluate the therapeutic efficacy of Liensinine combination with radiotherapy and immunotherapy.

Results: Liensinine inhibited HCC cell viability, migration, and proliferation, promoting apoptosis and shifting metabolism from glycolysis to oxidative phosphorylation. This metabolic reprogramming was linked to the activation of the AMPK-HIF-1α axis and increased ROS production. Furthermore, Liensinine induced Endoplasmic reticulum (ER) stress, as evidenced by elevated levels of CHOP and ATF4, which contributed to AMPK activation and suppression of HIF-1α. Liensinine reduced PD-L1 expression, enhanced M1 macrophage polarization, and promoted CD8 + T cell infiltration into tumors. In vivo, Liensinine significantly suppressed tumor growth, reduced vascular density, and reshaped the immune microenvironment by promoting M1 macrophage polarization. Combination therapy with Liensinine, radiotherapy, and immunotherapy resulted in synergistic effects, including enhanced tumor cell apoptosis, increased immune cell infiltration, and improved therapeutic efficacy.

Conclusion: Liensinine exerts potent antitumor effects in HCC by reprogramming tumor metabolism, inducing ER stress, enhancing immune responses, and modulating the TME. The combination of Liensinine with immunotherapy and radiotherapy significantly improves therapeutic efficacy, suggesting its potential as a novel treatment strategy for HCC.

Liensinine在肝细胞癌中通过AMPK-HIF-1α轴重编程代谢,重塑免疫微环境并增强免疫治疗。
背景:肝细胞癌(HCC)是癌症相关死亡的主要原因,晚期治疗选择有限。莲子碱,一种从莲子中提取的天然生物碱,已经显示出作为抗癌剂的前景。然而,其潜在的机制,特别是在调节肿瘤代谢和免疫反应方面,仍然知之甚少。本研究旨在探讨连辛碱在HCC中的抗肿瘤作用,重点关注其调节代谢途径、免疫反应和肿瘤微环境的能力。方法:肝细胞癌细胞系(HUH7和Hep1-6)经连体碱处理后,观察细胞活力、迁移、增殖和凋亡情况。通过RNA测序、海马代谢测定和葡萄糖/乳酸测量分析代谢重编程。用利连辛碱处理细胞的条件培养基处理THP-1巨噬细胞和外周血单个核细胞(PBMCs),研究其对免疫细胞的影响。在体内,采用皮下异种移植和原位肝癌模型,评价连辛碱联合放疗和免疫治疗的疗效。结果:连辛碱抑制HCC细胞活力、迁移和增殖,促进细胞凋亡,并将代谢从糖酵解转变为氧化磷酸化。这种代谢重编程与AMPK-HIF-1α轴的激活和ROS产生的增加有关。此外,lensinine诱导内质网(ER)应激,如CHOP和ATF4水平升高,这有助于AMPK的激活和HIF-1α的抑制。连辛碱降低PD-L1表达,增强M1巨噬细胞极化,促进CD8 + T细胞向肿瘤浸润。在体内,连辛碱通过促进M1巨噬细胞极化,显著抑制肿瘤生长,降低血管密度,重塑免疫微环境。连辛宁与放疗、免疫治疗联合治疗可产生协同效应,增强肿瘤细胞凋亡,增加免疫细胞浸润,提高治疗效果。结论:连辛碱通过重编程肿瘤代谢、诱导内质网应激、增强免疫反应、调节TME等途径在HCC中发挥了较强的抗肿瘤作用。Liensinine联合免疫治疗和放疗可显著提高治疗效果,提示其有潜力成为一种新的HCC治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信