Developing a Better Hepatocellular Carcinoma Treatment: AlEu MOF Nanoparticles Enhance Microwave Thermal Ablation and Synergistically Activate the cGAS-STING Pathway.

PURPOSE: To address the high recurrence rate of hepatocellular carcinoma (HCC) following microwave ablation (MWA) therapy, this study develops aluminum-europium metal-organic framework (AlEu MOF) nanoparticles that enhance MWA efficacy by physically improving thermal ablation and activating cyclic GMP-AMP (cGAMP) synthase-stimulator of interferon genes (cGAS-STING)-mediated antitumor immunity.

METHODS

AlEu MOF nanoparticles were synthesized via a one-pot hydrothermal method and characterized for physicochemical properties. Biocompatibility and in vitro cell-killing efficacy in combination with MWA were evaluated in Hepa1-6 cell lines. Immunostimulatory capacity was assessed by measuring activation markers of the cGAS-STING pathway. In vivo antitumor efficacy was investigated in a Hepa1-6 subcutaneous tumor-bearing mouse model, with monitoring of tumor growth, intratumoral temperature elevation, serum levels of cGAS-STING pathway downstream effectors, and treatment safety.

RESULTS

AlEu MOF nanoparticles demonstrated excellent biocompatibility and hemocompatibility. In combination with MWA, AlEu MOF significantly enhanced thermal efficiency within tumors, resulting in superior tumor growth inhibition compared with MWA alone. Mechanistically, the enhanced thermal ablation triggered mitochondrial damage and downstream cGAS-STING pathway activation, as evidenced by elevated serum levels of key downstream cytokines (IFN-γ, IL-6 and TNF-α) in the combination therapy group. No significant hepatorenal toxicity or major organ damage was observed throughout the treatment period.

CONCLUSION

The AlEu MOF nanoparticles potentiate MWA therapy through a dual synergistic mechanism: enhanced thermal ablation serves as the upstream trigger for cGAS-STING activation, while europium ions simultaneously amplify the STING signaling output, together converting local thermal ablation into systemic antitumor immunity. This synergistic strategy offers a promising approach for enhancing both local tumor ablation and systemic antitumor immunity in HCC.