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
靶向胶质瘤的奥沙利铂/铁蛋白笼形物通过劫持 Fe(2+) 并增强 Fenton 反应逆转免疫抑制微环境
英文原题：Glioma-targeted oxaliplatin/ferritin clathrate reversing the immunosuppressive microenvironment through hijacking Fe(2+) and boosting Fenton reaction.
查看英文原题
Glioma-targeted oxaliplatin/ferritin clathrate reversing the immunosuppressive microenvironment through hijacking Fe(2+) and boosting Fenton reaction.
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中文摘要
胶质瘤易对替莫唑胺（TMZ）产生耐药性。TMZ耐药胶质瘤分泌白细胞介素-10（IL-10）和转化生长因子-（TGF-），招募调节性T细胞（T reg）并抑制T细胞和NK 细胞（NK细胞）的活性，随后形成免疫抑制微环境。奥沙利铂（OXA）极大地抑制TMZ耐药胶质瘤细胞的增殖，但OXA穿越血脑屏障（BBB）的能力较弱。
因此，OXA对胶质瘤的治疗效果并不令人满意。转铁蛋白受体1（TfR1）在脑毛细血管内皮细胞和TMZ耐药胶质瘤细胞中高表达。
在本研究中，将OXA负载到铁蛋白（Fn）中，制备胶质瘤靶向的奥沙利铂/铁蛋白包合物OXA@Fn。OXA@Fn有效穿越BBB，并通过TfR1被TMZ耐药胶质瘤细胞主动摄取。随后，OXA增加细胞内H 2 O 2 水平并诱导TMZ耐药胶质瘤细胞凋亡。
同时，Fn增加TMZ耐药胶质瘤细胞中的Fe 2+ 水平。此外，膜铁转运蛋白1的表达显著降低，导致Fe 2+ 被锁在TMZ耐药胶质瘤细胞内。这随后增强了Fenton反应并促进了TMZ耐药胶质瘤细胞的铁死亡。
因此，T细胞介导的抗肿瘤免疫反应被强烈诱导，TMZ耐药胶质瘤组织中的免疫抑制微环境被显著逆转。最终，TMZ耐药胶质瘤的生长和侵袭被OXA@Fn抑制。OXA@Fn在TMZ耐药胶质瘤的治疗中显示出巨大潜力，并具有临床转化的前景。
展开英文摘要原文
Glioma is easy to develop resistance to temozolomide (TMZ). TMZ-resistant glioma secretes interleukin-10 (IL-10) and transforming growth factor- (TGF- ), recruiting regulatory T cell (T reg ) and inhibiting the activity of T cells and natural killer cell (NK cell), subsequently forming an immunosuppressive microenvironment. Oxaliplatin (OXA) greatly inhibits the proliferation of TMZ-resistant glioma cells, but the ability of OXA to cross blood-brain barrier (BBB) is weak.
Thus, the therapeutic effect of OXA on glioma is not satisfactory. Transferrin receptor 1 (TfR1) is highly expressed in brain capillary endothelial cells and TMZ-resistant glioma cells. In this study, OXA was loaded into ferritin (Fn) to prepare glioma-targeted oxaliplatin/ferritin clathrate OXA@Fn.
OXA@Fn efficiently crossed BBB and was actively taken up by TMZ-resistant glioma cells via TfR1. Then, OXA increased the intracellular H 2 O 2 level and induced the apoptosis of TMZ-resistant glioma cells. Meanwhile, Fn increased Fe 2+ level in TMZ-resistant glioma cells.
In addition, the expression of ferroportin 1 was significantly reduced, resulting in Fe 2+ to be locked up inside the TMZ-resistant glioma cells. This subsequently enhanced the Fenton reaction and boosted the ferroptosis of TMZ-resistant glioma cells.
Consequently, T cell mediated anti-tumor immune response was strongly induced, and the immunosuppressive microenvironment was significantly reversed in TMZ-resistant glioma tissue. Ultimately, the growth and invasion of TMZ-resistant glioma was inhibited by OXA@Fn. OXA@Fn shows great potential in the treatment of TMZ-resistant glioma and prospect in clinical transformation.
论文信息
- 作者
- Li X、Cheng Y、Yang Z、Ji Q、Huan M、Ye W、Liu M、Zhang B
- 第一作者单位
- Department of Pharmaceutics, School of Pharmacy, Air Force Medical University, Changle West Road 169, Xi'an, 710032, Shaanxi, China.China
- 通讯作者单位
- Department of Pharmaceutics, School of Pharmacy, Air Force Medical University, Changle West Road 169, Xi'an, 710032, Shaanxi, China. zhousy@fmmu.edu.cn.China
- 期刊
- Journal of nanobiotechnology2024 Mar 5
- 原文标识
- PubMed 38443927 · DOI 10.1186/s12951-024-02376-w