To improve antitumor immunity in cold tumors, Li et al. developed a single-agent mRNA nanomedicine comprising lipid nanoparticles (LNPs) containing mRNA encoding the N-terminal domain of pore-forming gasdermin (mRNA/LNPs) that mediates pyroptosis via inflammatory cytokine release and tumor necrosis. In multiple tumor models, intratumoral mRNA/LNPs induced tumor pyroptosis, eliciting robust antitumor immunity, prolonged survival, and enhanced responses to anti-PD-1. Triggering pyroptosis also suppressed tumor growth in distant, untreated tumors, suggesting this approach could improve immunotherapy in immunologically cold tumors.
Contributed by Katherine Turner
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.
Author Info: (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 D
Author Info: (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. xueqingzhang@sjtu.edu.cn. National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, PR China. xueqingzhang@sjtu.edu.cn. (3) Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, USA. (4) Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, PR China. National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, Shanghai, PR China. (5) Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ, USA. (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. xiaoyang.xu@njit.edu. Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ, USA. xiaoyang.xu@njit.edu.
