<br>锌有机金属框架疫苗控释 Zn2+ 调节肿瘤细胞外基质降解增强免疫治疗疗效,Advanced Science

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锌有机金属框架疫苗控释 Zn2+ 调节肿瘤细胞外基质降解增强免疫治疗疗效
Advanced Science ( IF 14.3 ) Pub Date : 2023-07-13 , DOI: 10.1002/advs.202302967
Lin Ding _{1,

2,

3} , Minli Liang _{1,

2,

3} , Yuanyuan Li ₄ , Mei Zeng ₅ , Meiting Liu ₅ , Wei Ma _{2,

3} , Fuming Chen _{2,

3} , Chenchen Li ₆ , Rui L Reis ₇ , Fu-Rong Li _{1,

2,

3} , Yanli Wang ₆

Affiliation

肿瘤细胞外基质（ECM）不仅形成T细胞浸润的物理屏障，还调节多种免疫抑制通路，是免疫治疗失败的重要原因。环磷酸鸟苷-磷酸腺苷合酶-干扰素基因刺激剂（cGAS-STING）通路在激活CD8 ⁺ T细胞、维持CD8 ⁺ T细胞干性和增强抗肿瘤作用中发挥关键作用。在此，报道了一种通过自组装制备的锌有机金属框架疫苗（ZPM@OVA-CpG），在酸性条件下实现了树突状细胞（DC）溶酶体和肿瘤微环境中Zn ²⁺的定点释放。该疫苗主动靶向DC，显着增强cGAS-STING信号，促进DC成熟和抗原交叉呈递，诱导CD8 ⁺ T细胞强烈激活。同时，疫苗到达肿瘤部位，释放Zn ²⁺ ，显着上调基质金属蛋白酶-2的活性，降解肿瘤ECM的多种胶原成分，有效缓解免疫抑制，显着增强CD8 ⁺的肿瘤浸润和杀伤作用。 T细胞。 ZPM@OVA-CpG疫苗不仅解决了抗原递送效率低、CD8 ⁺ T细胞激活能力弱的问题，而且首次通过疫苗实现了肿瘤ECM的降解，为肿瘤细胞的开发提供了一个有前景的治疗平台。高效的新型肿瘤疫苗。

"点击查看英文标题和摘要"

Zinc-Organometallic Framework Vaccine Controlled-Release Zn2+ Regulates Tumor Extracellular Matrix Degradation Potentiate Efficacy of Immunotherapy

Tumor extracellular matrix (ECM) not only forms a physical barrier for T cells infiltration, but also regulates multiple immunosuppressive pathways, which is an important reason for immunotherapy failure. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway plays a key role in activating CD8⁺ T cells, maintaining CD8⁺ T cells stemness and enhancing the antitumor effect. Herein, a zinc-organometallic framework vaccine (ZPM@OVA-CpG) prepared by self-assembly, which achieves site-directed release of Zn²⁺ in dendritic cell (DC) lysosomes and tumor microenvironment under acidic conditions, is reported. The vaccine actively targets DC, significantly enhances cGAS-STING signal, promotes DC maturation and antigen cross-presentation, and induces strong activation of CD8⁺ T cells. Meanwhile, the vaccine reaches the tumor site, releasing Zn²⁺, significantly up-regulates the activity of matrix metalloproteinase-2, degrades various collagen components of tumor ECM, effectively alleviates immune suppression, and significantly enhances the tumor infiltration and killing of CD8⁺ T cells. ZPM@OVA-CpG vaccine not only solves the problem of low antigen delivery efficiency and weak CD8⁺ T cells activation ability, but also achieves the degradation of tumor ECM via the vaccine for the first time, providing a promising therapeutic platform for the development of efficient novel tumor vaccines.

更新日期：2023-07-13

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