Disrupting fumarylacetoacetate hydrolase by stratified nanoplatforms orchestrates metabolic-immune reprogramming and...

Hepatocellular carcinoma (HCC) recurrence following microwave ablation poses a pressing clinical challenge, driven by metabolically adapted residual cells that establish an immunosuppressive tumour microenvironment. Our study identifies the post-ablation upregulation of fumarylacetoacetate hydrolase (FAH) as a crucial "metabolic checkpoint" promoting relapse. Elevated FAH expression results in increased fumarate levels within residual HCC cells, supporting tumour cell survival by enhancing energy metabolism while concurrently impairing CD8⁺ T cell function. Mechanistically, fumarate binds to and stabilises heat shock protein 70 (HSP70), establishing a thermal ablation induced FAH-fumarate-HSP70 axis that drives immunosuppression. To counteract this pivotal axis, we engineered a gallium-based functionalized nanoplatform. This system incorporates a lactate oxidase shell that responds to the lactate-rich tumour microenvironment, enabling the site-specific co-release of Ga³⁺, FAH-silencing plasmids and the glycolysis inhibitor 2-deoxy-D-glucose. Our nanoplatforms disrupt the FAH-fumarate-HSP70 axis to eradicate residual HCC, activate CD8⁺ T cells, and restore immunity, targeting recurrence dysregulation while integrating metabolic blockade with immunomodulation to prevent post-ablation relapse with clinical translation potential.