Mitochondrial transfer in the HSC-HCC-macrophage network shapes hepatocellular carcinoma progression

• 成果类型: Article
• 署名作者: Zhang, La; Ren, Cong; He, Miao; Chen, Xinyu; Liu, Hongqing; Liu, Yilin; Luo, Jing; Li, Zhenghang; Wang, Jianwei; Miao, Wenjun; Peng, Qiling; Jiang, Ning
• 署名单位: Chongqing Medical University; Chongqing Medical University; Chongqing Medical University; Chongqing University; Chongqing Medical University; Chongqing Medical University; Chongqing Medical University; Chongqing Medical University; Chongqing Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2512592123
• 发表日期: 2026-02-10
• 页码: e2512592123
• 关键词: hepatocellular carcinoma; mitochondrial transfer; tunneling nanotube; extracellularvesicle; nano-therapy; cell; metabolism

摘要

Mitochondrial crosstalk between tumor cells and components of the tumor microenvironment (TME) is a critical yet underexplored mechanism driving hepatocellular carcinoma (HCC) progression. Here, we demonstrate that in HCC, mitochondria can be transferred from hepatic stellate cells to cancer cells via tunneling nanotubes (TNTs), supplying essential energy for tumor growth. Simultaneously, cancer cells offload damaged mitochondria to macrophages through extracellular vesicles (EVs), facilitating their clearance and promoting tumor development. To disrupt this mitochondrial exchange, we developed a responsive liposomal nanocarrier (L&G@LipoPPV) coencapsulating L-778123 and GW4869 to simultaneously inhibit TNT-mediated and vesicle-mediated mitochondrial transfer. Tis work provides the first comprehensive evidence of mitochondrial transfer dynamics in the TME, with tumor cells as the central hub, and highlights L&G@LipoPPV as an innovative and effective strategy to block mitochondrial crosstalk. Our findings address critical challenges of drug solubility and delivery, offering a rational approach to reprogram the TME and suppress liver cancer progression.