Disrupting fumarylacetoacetate hydrolase by stratified nanoplatforms orchestrated metabolic-immune reprogramming and prevent post-ablation HCC relapse

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 intra- and extracellular fumarate levels within residual HCC cells, supporting tumour cell survival by enhancing Krebs cycle activity while concurrently impairing CD8⁺ T cell function. Mechanistically, fumarate binds to and stabilises heat shock protein 70 (HSP70), establishing an ablation-induced FAH–fumarate–HSP70 axis that drives immunosuppression. To counteract this pivotal axis, we engineered a novel 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 FAH-silencing plasmids and the glycolysis inhibitor 2-deoxy-D-glucose. Our stratified nanoplatforms, designed to disrupt the FAH–fumarate–HSP70 axis, achieve synergistic eradication of residual HCC cells, promote CD8⁺ T cell activation, and restore anti-tumour immunity through coordinated metabolic intervention. This unique design specifically targets the metabolic and immune dysregulation underlying HCC recurrence, integrating metabolic blockade with immunomodulation to offer a highly effective strategy for preventing post-ablation relapse and holds significant potential for clinical translation.