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<p>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<sup>+</sup> 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 Ga<sup>3+</sup>, 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<sup>+</sup> T cells, and restore immunity, targeting recurrence dysregulation while integrating metabolic blockade with immunomodulation to prevent post-ablation relapse with clinical translation potential.</p>

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Disrupting fumarylacetoacetate hydrolase by stratified nanoplatforms orchestrates metabolic-immune reprogramming and prevents post-ablation HCC relapse

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Zhiwen Hong,
  • Xiaolong Liu,
  • Rouhan A,
  • Zengzhen Chen,
  • Qianjiang Wu,
  • Jixian Fu,
  • Xue Guan,
  • Can Wang,
  • Xinghua Wang,
  • Shan Jiang,
  • Bolong Li,
  • Zhaobo Wang,
  • Lei Zhang,
  • Xianwei Meng,
  • Yali Cui,
  • Tengchuang Ma

摘要

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.