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已发表论文
酶指导自组装肽打击线粒体用于有效的免疫原性抗肿瘤治疗
Authors Zhao J, Tian S, Li P, Wu H, Li S , Yuan H
Received 2 June 2025
Accepted for publication 29 October 2025
Published 6 November 2025 Volume 2025:20 Pages 13421—13435
DOI https://doi.org/10.2147/IJN.S544253
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Professor Farooq A. Shiekh
Jingyuan Zhao,1,* Siyu Tian,1,* Pengfei Li,2 Huanhuan Wu,2 Shuai Li,1,3 Hong Yuan1
1Clinical Laboratory Center, Central Hospital of Dalian University of Technology, Dalian, People’s Republic of China; 2College of Laboratory Medicine, Dalian Medical University, Dalian, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Shuai Li, Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China, Email shuaili2015@outlook.com Hong Yuan, Clinical Laboratory Center, Central Hospital of Dalian University of Technology, Dalian, People’s Republic of China, Email yuanhonglab@163.com
Introduction: Immunogenic cell death (ICD) plays a crucial role in cancer immunotherapy in disrupting the immunosuppressive tumor microenvironment (TME). However, key bottlenecks remain, including the lack of precise and efficient ICD induction at the tumor site and poor synergy with other therapeutic mechanisms for tumor suppression.
Methods: To tackle these bottlenecks, this study developed a legumain-instructed self-assembling peptide PSK, with legumain highly expressed in tumors. Its mechanism is as follows: first, via sequence design, it specifically binds to programmed cell death ligand 1 (PD-L1), which highly expressed on tumor cells, mediating its selective uptake by tumor cells. Subsequently, catalyzed cleavage by legumain in the TME triggers its in-situ self-assembly into nanoaggregates, prolonging its retention at the tumor site. Finally, the PSK targets the mitochondria of tumor cells, enabling precise organelle-level action.
Results: In vitro and in vivo experiments showed that PSK exerts synergistic anti-tumor effects through a dual mechanism: it targets mitochondria to disrupt membrane potential and induce dysfunction, thereby triggering tumor cell ICD and releasing damage-associated molecular patterns (DAMPs) to activate immunity; meanwhile, it binds to PD-L1 to downregulate its expression, reducing tumor immune escape. As an enzyme-responsive in-situ self-assembling peptide drug, PSK exhibits high tumor cell selectivity, effectively inhibits tumor growth, and has no obvious systemic toxicity.
Discussion: The development of PSK provides a new approach for anti-tumor peptide drug research and precision tumor therapy. With its design featuring tumor specificity, enzyme responsiveness, and dual-action mechanism, this peptide is expected to address key challenges in ICD-based cancer immunotherapy.
Keywords: immunogenic cell death, in-situ assembling, mitochondrial, peptide
1Clinical Laboratory Center, Central Hospital of Dalian University of Technology, Dalian, People’s Republic of China; 2College of Laboratory Medicine, Dalian Medical University, Dalian, People’s Republic of China; 3Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Shuai Li, Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China, Email shuaili2015@outlook.com Hong Yuan, Clinical Laboratory Center, Central Hospital of Dalian University of Technology, Dalian, People’s Republic of China, Email yuanhonglab@163.com
Introduction: Immunogenic cell death (ICD) plays a crucial role in cancer immunotherapy in disrupting the immunosuppressive tumor microenvironment (TME). However, key bottlenecks remain, including the lack of precise and efficient ICD induction at the tumor site and poor synergy with other therapeutic mechanisms for tumor suppression.
Methods: To tackle these bottlenecks, this study developed a legumain-instructed self-assembling peptide PSK, with legumain highly expressed in tumors. Its mechanism is as follows: first, via sequence design, it specifically binds to programmed cell death ligand 1 (PD-L1), which highly expressed on tumor cells, mediating its selective uptake by tumor cells. Subsequently, catalyzed cleavage by legumain in the TME triggers its in-situ self-assembly into nanoaggregates, prolonging its retention at the tumor site. Finally, the PSK targets the mitochondria of tumor cells, enabling precise organelle-level action.
Results: In vitro and in vivo experiments showed that PSK exerts synergistic anti-tumor effects through a dual mechanism: it targets mitochondria to disrupt membrane potential and induce dysfunction, thereby triggering tumor cell ICD and releasing damage-associated molecular patterns (DAMPs) to activate immunity; meanwhile, it binds to PD-L1 to downregulate its expression, reducing tumor immune escape. As an enzyme-responsive in-situ self-assembling peptide drug, PSK exhibits high tumor cell selectivity, effectively inhibits tumor growth, and has no obvious systemic toxicity.
Discussion: The development of PSK provides a new approach for anti-tumor peptide drug research and precision tumor therapy. With its design featuring tumor specificity, enzyme responsiveness, and dual-action mechanism, this peptide is expected to address key challenges in ICD-based cancer immunotherapy.
Keywords: immunogenic cell death, in-situ assembling, mitochondrial, peptide