Funding
National Natural Science Foundation of China (NSFC)
Innovative Research Team of High-level Local University in Shanghai (Innovative Research Team of High-level Local Universities in Shanghai)
Shanghai Jiao Tong University School of Medicine
Renji Hospital, Shanghai Jiao Tong University School of Medicine
ARTICLE ABSTRACT
Local immunotherapy stimulates immune responses against tumors while avoiding adverse effects associated with systemic administration. However, current strategies for tumor-targeted in situ immunotherapy are still limited. mRNA-based gene therapy represents a promising strategy. Gasdermin E (GSDME)–mediated pyroptosis is reported to exert antitumor immunity. In this study, we synthetized mRNA encoding GSDME encapsulated by lipid nanoparticles (LNP-Gsdme). In situ delivery of LNP-Gsdme through intratumoral injection suppressed tumor growth, boosted monocyte infiltration, and activated CD8+T cells. LNP-Gsdme induced immunogenic cell death in tumor cells, releasing creatine as a metabolic damage-associated molecular pattern. Creatine elicited the cGAMP–STING–type I IFN signaling pathway in monocytes and reprogrammed intratumoral monocytes toward an immunostimulatory phenotype, consequently potentiating CD8+ T cell–mediated antitumor immune responses. Furthermore, creatine supplementation enhanced the antitumor efficacy of LNP-Gsdme. Our study uncovers creatine as an important metabolic biomarker of pyroptosis-induced immunogenic cell death in tumors, providing new insights and a promising therapeutic approach for in vivo mRNA-based immunotherapies for cancer.
