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

• Published in: Nature communications Vol. 14; no. 1; pp. 4223 - 16
• Main Authors: Li, Fengqiao, Zhang, Xue-Qing, Ho, William, Tang, Maoping, Li, Zhongyu, Bu, Lei, Xu, Xiaoyang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.07.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/21; 13/31; 14/19; 38; 42; 59; 59/5; 631/61/201; 631/61/350/354; 631/61/54/992; 631/67/1059/2325; 631/67/327; 64; 64/60; Animal models; Animals; Anticancer properties; Antitumor activity; Cancer; Cancer immunotherapy; Cancer therapies; Cold; Feedback loops; Female; Gasdermins; Gene therapy; Humanities and Social Sciences; Immune response; Immunity; Immunotherapy; Lipids; Lymphocytes T; Mice; mRNA; multidisciplinary; N-Terminus; Nanoparticles; Nanotechnology; Neoplasms; PD-1 protein; Positive feedback; Pyroptosis; Science; Science (multidisciplinary); Tumor Microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39938-9

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. mRNA nanomedicine-based gene therapy may offer opportunities for cancer treatment. Here the authors show that mRNA lipid nanoparticles encoding the N-terminal domain of gasdermin B trigger pyroptosis and promote anti-tumor immune responses in preclinical cancer models.