A DNA/DMXAA/Metal-Organic Framework Activator of Innate Immunity for Boosting Anticancer Immunity.

Area of Science:

• Biomedical Engineering
• Immunology
• Materials Science

Background:

• Immunotherapy shows promise but faces challenges in treating highly vascularized hepatocellular carcinoma (HCC).
• Metal-organic framework-801 (MOF-801) has potential applications beyond drug delivery, including immune system modulation.
• Targeting the tumor microenvironment and vascularization is crucial for effective HCC treatment.

Purpose of the Study:

• To investigate MOF-801's role as a stimulator of interferon genes (STING) via Toll-like receptor 4 (TLR4).
• To develop a nanoparticle (MOF-CpG-DMXAA) for synergistic HCC immunotherapy by combining MOF-801 with STING agonists.
• To evaluate the therapeutic efficacy of MOF-CpG-DMXAA in preclinical HCC models.

Main Methods:

• MOF-801 was utilized as a STING activator through TLR4.
• CpG oligodeoxynucleotides (CpG ODNs) and 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) were co-assembled with MOF-801 into nanoparticles.
• The nanoparticles were tested in HCC-bearing mouse models to assess immune activation and therapeutic effects.

Main Results:

• MOF-CpG-DMXAA nanoparticles effectively delivered CpG ODNs and DMXAA, reprogramming tumor-associated macrophages (TAMs) and promoting dendritic cell (DC) maturation.
• The nanoparticles demonstrated vascular disrupting functions, improving the tumor microenvironment.
• Systemic immune activation and robust tumoricidal immunity were observed, leading to superior therapeutic efficiency in orthotopic and recurrent HCC models.

Conclusions:

• MOF-801 functions as a STING activator, offering a novel approach for HCC immunotherapy.
• The developed MOF-CpG-DMXAA nanoparticles provide a synergistic strategy for enhancing the tumor immune microenvironment and vascular disruption.
• This approach shows significant potential for treating challenging HCC cases, including orthotopic and recurrent forms.