靶向多胺代谢诱导氧化/羰基应激,重振前列腺癌抗肿瘤免疫

IF 11.5 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Aijing Zhang , Jianguo Zheng , Yingying Xu , Shuai Fu , Qinglong Du , Chengyang Zhao , Yuxiang Meng , Mengqi Li , Lin Wang , Shuliang Wang , Tongrui Shi , Chen Yang , Peihong Jiang , Yiping Wang , Zhongwei Zhao , Zhao Zhang , Shuo Zhao , Xin Qin , Huimin Geng , Nengwang Yu
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引用次数: 0

摘要

由于肿瘤微环境(TME)的免疫抑制特性,前列腺癌(PCa)的免疫治疗仍然具有挑战性。氧化损伤增强免疫原性细胞死亡(ICD)以抵消前列腺癌的免疫治疗抵抗,但受肿瘤抗氧化防御和TME中单模态活性氧(ROS)产生的限制。在此,我们报告了一种基于多胺的创新策略,该策略通过过量产生过氧化氢和丙烯醛来同时诱导氧化/羰基应激,同时抑制内源性抗氧化系统,从而协同放大氧化/羰基损伤,从而触发强大的ICD并获得有效的抗肿瘤功效。体外和体内实验均表明,经pca靶向肽修饰的纳米颗粒可产生丙烯醛,诱导线粒体破坏、DNA损伤和脂质过氧化积累。此外,它们增强了TME内成熟树突状细胞和T细胞的募集,从而抑制肺转移和肿瘤再挑战。本研究提出了一种利用多胺代谢诱导羰基和氧化联合应激的免疫治疗策略,为克服晚期前列腺癌的冷TME抗性提供了一种新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Targeting polyamine metabolism induces oxidative/carbonyl stress to reinvigorate antitumor immunity in prostate cancer

Targeting polyamine metabolism induces oxidative/carbonyl stress to reinvigorate antitumor immunity in prostate cancer

Targeting polyamine metabolism induces oxidative/carbonyl stress to reinvigorate antitumor immunity in prostate cancer
Immunotherapy of prostate cancer (PCa) remains challenging due to the immunosuppressive nature of the tumor microenvironment (TME). Oxidative damage enhances immunogenic cell death (ICD) to counteract immunotherapy resistance in PCa, but is limited by tumor antioxidant defenses and single-modality reactive oxygen species (ROS) generation in the TME. Herein, we report an innovative polyamine-based strategy that overproduces hydrogen peroxide and acrolein to simultaneously induce oxidative/carbonyl stress while suppressing endogenous antioxidant systems, thereby synergistically amplifying oxidative/carbonyl damage, which triggers robust ICD and achieves potent antitumor efficacy. Both in vitro and in vivo assays demonstrated that the nanoparticles, modified with a PCa-targeting peptide, could generate acrolein to induce mitochondrial destruction, DNA damage, and accumulate lipid peroxidation. In addition, they enhanced the recruitment of mature dendritic cells and T cells within the TME, thus inhibiting lung metastasis and tumor rechallenge. This work proposes an immunotherapy strategy using polyamine metabolism to induce combined carbonyl and oxidative stress, providing a novel approach for overcoming cold TME resistance in advanced PCa.
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来源期刊
Journal of Controlled Release
Journal of Controlled Release 医学-化学综合
CiteScore
18.50
自引率
5.60%
发文量
700
审稿时长
39 days
期刊介绍: The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System. Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries. Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.
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