RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
一种用于缺氧响应性共递送 NQO1 酶响应性紫檀芪前药和非铂类铂配合物 phenanthriplatin 的纳米平台，用于多机制宫颈癌治疗
英文原题：A nanoplatform for hypoxia-responsive co-delivery of an NQO1 enzyme-responsive pterostilbene prodrug and phenanthriplatin for multi-mechanistic cervical cancer therapy.
查看英文原题
A nanoplatform for hypoxia-responsive co-delivery of an NQO1 enzyme-responsive pterostilbene prodrug and phenanthriplatin for multi-mechanistic cervical cancer therapy.
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中文摘要
基于铂的纳米颗粒疗法主要通过激活凋亡通路来消除宫颈癌（CC）细胞。然而，其疗效受到实体瘤缺氧微环境的显著限制。为解决这一局限性，我们开发了一种可变尺寸纳米聚合物（PAP 3.5），基于PAMAM 3.5代、偶氮苯（AZO）作为缺氧敏感连接子以及聚乙二醇（PEG）作为屏蔽层。该系统共递送菲铂（Phen-Pt）及其增敏剂。
值得注意的是，紫檀芪（PTS）被鉴定为一种新型天然组蛋白去乙酰化酶抑制剂（HDACi），可增强Phen-Pt诱导的DNA损伤。
此外，我们设计了一种醌结构的PTS前药（PTS-433），其在过表达NADPH：醌氧化还原酶1（NQO1）的CC细胞中选择性释放PTS，而在正常细胞中保持惰性。
此外，PTS-433恢复了缺氧肿瘤微环境（TME）中自然杀伤（NK）细胞的活性，克服了免疫抑制。在HeLa细胞荷瘤小鼠模型中，PAP 3.5/Phen-Pt/PTS-433系统表现出显著的肿瘤生长抑制，为CC提供了一种多模式治疗策略。
展开英文摘要原文
Platinum-based nanoparticle therapies primarily eliminate cervical cancer (CC) cells by activating the apoptosis pathway.
However, their efficacy is significantly hindered by the hypoxic microenvironment of solid tumors. To address this limitation, we developed a variable-size nano-polymer (PAP 3. 5) based on PAMAM 3. 5 generation, azobenzene (AZO) as a hypoxia-sensitive linker and polyethylene glycol (PEG) as a shielding layer. This system co-delivers phenanthriplatin (Phen-Pt) and its sensitizer.
Notably, pterostilbene (PTS) was identified as a novel natural histone deacetylase inhibitor (HDACi), enhancing Phen-Pt-induced DNA damage.
Additionally, we designed a quinone-structured PTS prodrug (PTS-433) that selectively releases PTS in CC cells overexpressing NADPH: quinone oxidoreductase 1 (NQO1), while remaining inert in normal cells.
Furthermore, PTS-433 restored the activity of natural killer (NK) cells in the hypoxic tumor microenvironment (TME), overcoming immune suppression. In a HeLa cell tumor-bearing mouse model, the PAP 3. 5/Phen-Pt/PTS-433 system demonstrated significant tumor growth inhibition, offering a multi-modal therapeutic strategy for CC.
论文信息
- 作者
- Li Z、Zhao Z、Zhang Y、Xie Z、Zhang J、Jin X、Zhang Z、Sun S
- 第一作者单位
- Shihezi University College of Chemistry and Chemical Engineering, Shihezi, 832002, Xinjiang, China. Electronic address: 1667754715@qq.com.China
- 通讯作者单位
- Key Laboratory of Xinjiang Endemic Phytomedicine Resources Ministry of Education, Shihezi University College of Pharmacy, Shihezi, 832003, Xinjiang, China. Electronic address: dxl_pha@shzu.edu.cn.China
- 期刊
- Biochimica et biophysica acta. Molecular cell research2026 Jun
- 原文标识
- PubMed 41962774 · DOI 10.1016/j.bbamcr.2026.120145