TY - JOUR
T1 - mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy
AU - Li, Fengqiao
AU - Zhang, Xue Qing
AU - Ho, William
AU - Tang, Maoping
AU - Li, Zhongyu
AU - Bu, Lei
AU - Xu, Xiaoyang
N1 - Funding Information:
X.X. acknowledges funding from National Science Foundation (2001606) and American Heart Association grant #19AIREA34380849. This research is also supported by the Gustavus and Louise Pfeiffer Research Foundation Award. X.-Q. Z. acknowledges funding from the “Open Competition to Select the Best Candidates” Key Technology Program for Nucleic Acid Drugs of NCTIB (Grant No. NCTIB2022HS02002), the Natural Science Foundation of Shanghai (23ZR1427600), Shanghai Jiao Tong University Scientific and Technological Innovation Funds (2019TPA10), Foundation of National Facility for Translational Medicine (Shanghai) (TMSK-2020-008), and the Interdisciplinary Program of Shanghai Jiao Tong University [project number ZH2018ZDA36 (19×190020006)].
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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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U2 - 10.1038/s41467-023-39938-9
DO - 10.1038/s41467-023-39938-9
M3 - Article
C2 - 37454146
AN - SCOPUS:85164756256
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4223
ER -