Autophagy inhibitor-sensitized artificially activated neutrophils against hepatocellular carcinoma.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-06-18 eCollection Date: 2025-01-01 DOI:10.7150/thno.106404
Caixia Yang, Huang Yang, Zhengwei Mao, Weilin Wang, Yuan Ding
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引用次数: 0

Abstract

The use of activated neutrophils has emerged as a promising antineoplastic method in oncology. However, challenges, including a short lifespan, susceptibility to the tumor microenvironment, and protumorigenic risks, limit their clinical application. While artificial neutrophils have several limitations, few tumor-related studies have been conducted with constraining factors, including specific targeting inefficiency, immunogenicity and manufacturing challenges. Neutrophil elastase (ELANE), a key antitumor effector in activated neutrophils, is functionally mimicked by porcine pancreatic elastase (PPE), which exhibits selective cancer cytotoxicity. However, PPE triggers protective autophagy in hepatocellular carcinoma (HCC), limiting its therapeutic effectiveness. Methods: To overcome this resistance, we sensitized PPE by the autophagy inhibitor 3-methyladenine (3MA), which is codelivered via tumor-targeting liposomes. This system protects drugs and improves therapeutic efficacy both in vitro and in vivo. Results: 3MA enhanced iron-related ROS-mediated cell destruction induced by PPE while suppressing prosurvival autophagy. The autophagy inhibitor-sensitized artificially activated neutrophils (asAN-P/3) showed precise tumor targeting, excellent therapeutic efficacy, prolonged survival and favorable biocompatibility. Conclusions: We established a precise neutrophil-related tumor therapeutic method (asAN-P/3) and elucidated the mechanistic insights into PPE-mediated therapeutic limitations in HCC. Our study provides a substantial framework for the development of neutrophil-derived antitumor therapeutic strategies in oncology.

自噬抑制剂致敏的人工激活中性粒细胞抗肝癌。
使用活化的中性粒细胞已成为一种很有前途的肿瘤治疗方法。然而,包括寿命短、对肿瘤微环境的易感性和致原性风险在内的挑战限制了它们的临床应用。虽然人工中性粒细胞有一些局限性,但很少有与肿瘤相关的研究受到限制因素的影响,包括特异性靶向效率低下、免疫原性和制造挑战。中性粒细胞弹性酶(ELANE)是活化中性粒细胞中的一种关键抗肿瘤效应物,猪胰腺弹性酶(PPE)在功能上模仿它,表现出选择性的肿瘤细胞毒性。然而,PPE在肝细胞癌(HCC)中引发保护性自噬,限制了其治疗效果。方法:为了克服这种耐药性,我们用自噬抑制剂3-甲基腺嘌呤(3MA)致敏PPE,通过肿瘤靶向脂质体共递送。该系统保护药物,提高体内和体外的治疗效果。结果:3MA增强PPE诱导的铁相关ros介导的细胞破坏,同时抑制促生存自噬。自噬抑制剂致敏的人工活化中性粒细胞(asAN-P/3)具有肿瘤靶向性强、治疗效果好、存活时间长、生物相容性好等特点。结论:我们建立了一种精确的中性粒细胞相关肿瘤治疗方法(asAN-P/3),并阐明了ppe介导的HCC治疗局限性的机制。我们的研究为肿瘤中性粒细胞衍生的抗肿瘤治疗策略的发展提供了实质性的框架。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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