mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy

  • Nat Commun. 2023 Jul 15;14(1):4223. doi: 10.1038/s41467-023-39938-9.
Fengqiao Li  1 ,  Xue-Qing Zhang  2  3 ,  William Ho  1 ,  Maoping Tang  4  5 ,  Zhongyu Li  1 ,  Lei Bu  6 ,  Xiaoyang Xu  7  8
Affiliations
  • 1. Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, USA.
  • 2. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, PR China. [email protected].
  • 3. National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, PR China. [email protected].
  • 4. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, PR China.
  • 5. National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, PR China.
  • 6. Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA.
  • 7. Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, USA. [email protected].
  • 8. Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, USA. [email protected].
PMID: 37454146 DOI: 10.1038/s41467-023-39938-9
Abstract

Synergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold Tumors, yet current treatments often fail to induce a cascade of cancer-immunity cycle for effective antitumor immunity. Gasdermin-mediated Pyroptosis is a newly discovered mechanism in Cancer immunotherapy; however, cleavage in the N terminus is required to activate Pyroptosis. Here, we report a single-agent mRNA nanomedicine-based strategy that utilizes mRNA Lipid Nanoparticles (LNPs) encoding only the N-terminus of gasdermin to trigger Pyroptosis, eliciting robust antitumor immunity. In multiple female mouse models, we show that pyroptosis-triggering mRNA/LNPs turn cold Tumors into hot ones and create a positive feedback loop to promote antitumor immunity. Additionally, mRNA/LNP-induced Pyroptosis sensitizes Tumors to anti-PD-1 immunotherapy, facilitating tumor growth inhibition. Antitumor activity extends beyond the treated lesions and suppresses the growth of distant Tumors. We implement a strategy for inducing potent antitumor immunity, enhancing immunotherapy responses in immunologically cold Tumors.

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