2. Academic Validation
  3. Mitochondrial rewiring with small-molecule drug-free nanoassemblies unleashes anticancer immunity

Mitochondrial rewiring with small-molecule drug-free nanoassemblies unleashes anticancer immunity

  • Nat Commun. 2024 Sep 3;15(1):7664. doi: 10.1038/s41467-024-51945-y.
Lulu Ren 1 2,  Jianqin Wan 1,  Xiaoyan Li 1 3,  Jie Yao 1 3,  Yan Ma 1,  Fanchao Meng 1,  Shusen Zheng 4,  Weidong Han 5,  Hangxiang Wang 6 7 8
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China.
  • 2 Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, PR China.
  • 3 Department of Chemical Engineering, Zhejiang University, Hangzhou, Zhejiang Province, PR China.
  • 4 The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China. shusenzheng@zju.edu.cn.
  • 5 Department of Colorectal Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, PR China. hanwd@zjcc.org.cn.
  • 6 The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China. wanghx@zju.edu.cn.
  • 7 Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong Province, PR China. wanghx@zju.edu.cn.
  • 8 Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang Province, PR China. wanghx@zju.edu.cn.
PMID: 39227567 DOI: 10.1038/s41467-024-51945-y
Abstract

The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes Apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic Cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless Cancer therapy and overcome immunosuppression in cancers.

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