In situ delivery of Gasdermin E mRNA promotes antitumor immunity via creatine-elicited type Ⅰ interferon signaling in monocytes.
Study Goal
The researchers aimed to determine whether creatine, released during pyroptosis-induced immunogenic cell death, could enhance anti-tumor immune responses when combined with mRNA-based immunotherapy.
Results Summary
The study found that creatine acted as a metabolic damage-associated molecular pattern, activating the cGAMP-STING pathway in monocytes and promoting an immunostimulatory phenotype, which enhanced CD8+T cell-mediated anti-tumor effects. Creatine supplementation further improved the efficacy of the mRNA-based therapy.
Population
Tumor-bearing models (not specified if human or animal, but likely preclinical based on methodology).
Effective Dosage
Not specified
Duration
Not specified
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
in situ delivery of LNP-Gsdme through intratumoral injection | decrease | tumor growth | - | - | suppressed | #1 |
in situ delivery of LNP-Gsdme through intratumoral injection | increase | monocyte infiltration | - | - | boosted | #2 |
in situ delivery of LNP-Gsdme through intratumoral injection | increase | CD8+T cells | - | - | activated | #3 |
LNP-Gsdme | increase | immunogenic cell death (ICD) in tumor cells | - | - | induced | #4 |
Creatine | increase | cGAMP-STING-type I interferon signaling pathway in monocytes | - | - | elicited | #5 |
Creatine | increase | intratumoral monocytes toward an immunostimulatory phenotype | - | - | reprogrammed | #6 |
Creatine | increase | CD8+T cell-mediated anti-tumor immune responses | - | - | potentiating | #7 |
creatine supplementation | increase | the antitumor efficacy of LNP-Gsdme | - | - | enhanced | #8 |
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 anti-tumor immunity. Here, 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 (ICD) in tumor cells, releasing creatine as a metabolic damage-associated molecular pattern. Creatine elicited cGAMP-STING-type I interferon signaling pathway in monocytes and reprogrammed intratumoral monocytes toward an immunostimulatory phenotype, consequently potentiating CD8+T cell-mediated anti-tumor immune responses. Furthermore, creatine supplementation enhanced the antitumor efficacy of LNP-Gsdme. Our study uncovers creatine as an important metabolic biomarker of pyroptosis-induced ICD in tumors, providing new insights and a promising therapeutic approach for in vivo mRNA-based immunotherapies for cancer.