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

Abstract

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.

Regulation of anti-tumor immunity by metal ion in the tumor microenvironment

“…Moreover, a Zn-metal-organic skeleton vaccine (ZPM@OVA-CpG) achieved the targeted release of Zn 2+ in DCs and the TME under acidic conditions. The vaccine actively promoted DCs maturation and antigen cross-presentation via cGAS-STING signaling, resulting in the activation of CD8 + T cells ( 94 ). Weichselbaum et al.…”

“…actively promoted DCs maturation and antigen cross-presentation via cGAS-STING signaling, resulting in the activation of CD8 + T cells (94). Weichselbaum et al investigated ZnCDA, a powerful tumor-targeting STING agonist, which enhances tumor accumulation by destroying endothelial cells in the tumor vascular system.…”

Nanoengineering of Vaccine Nanoparticles via Templating of Metal–Organic Frameworks for Tumor Immunotherapy

“…Compared to other template materials, MOFs have been considered as ideal templates based on their high specific surface areas and high porosity . Particularly, zeolitic imidazolate framework (ZIF-8), composed of zinc ions and 2-methylimidazolate, exhibited excellent advantages as template material in nanoparticle fabrication due to the high loading capability, mild removal condition and pH-responsive dissociation. − Works from our lab and others showed that using ZIF-8 NPs as templates to prepare nanoparticles could achieve effective loading of payloads and intracellular delivery. − Additionally, poly­(ethylene glycol) (PEG) could act as a mineralizer to improve the dispersity, stability, and cargo loading capacities of ZIF-8 NPs. − …”