A novel mRNA-based multi-cytokine strategy to reprogram the peritoneal tumor microenvironment in ovarian cancer

BACKGROUND: Peritoneal dissemination is a hallmark feature of advanced ovarian cancer and significantly contributes to its poor prognosis. An intraperitoneal mRNA-based immunotherapy delivering a combination of single-chain interleukins (IL), including IL-12, IL-15, pro-IL-18, and Caspase-1, encapsulated in lipid nanoparticles, is administered to reprogram the immunosuppressive tumor microenvironment (TME) in a syngeneic ID8-Fluc ovarian cancer mouse model. RESULTS: This mRNA cocktail effectively suppresses tumor growth, reduces malignant ascites, and inhibits metastasis. Immune profiling reveals enhanced infiltration of effector CD8⁺ and CD4⁺ T cells, reduced regulatory T cells, and decreased expression of exhaustion markers such as TIM-3 and PD-1. Macrophage populations are shifted from immunosuppressive M2 to proinflammatory M1 phenotypes, with increased monocyte infiltration, indicating robust myeloid reprogramming. Although mRNA-expressed IL-12 monotherapy exhibits potent antitumor effects, the combination of IL-15, IL-18, and Caspase-1 elicits superior therapeutic efficacy. Although high-dose treatment induces hepatotoxicity and weight loss, a reduced-dose regimen maintains efficacy with improved safety. CONCLUSIONS: This study demonstrates the therapeutic potential of mRNA-based cytokine combinations to transform the ovarian cancer immune landscape. The modularity, localized delivery, and tunable expression of this platform provide a compelling framework for future mRNA immunotherapies targeting solid tumors with immunosuppressive TMEs.