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Background <p>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.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Yu-Sun Lee,
  • Jisun Lee,
  • Yeeun Lee,
  • Hyunho Yoon,
  • Seo-Hyeon Bae,
  • Subin Yoon,
  • Seonghyun Lee,
  • Gahyun Roh,
  • Youngran Cho,
  • Seongje Cho,
  • Dahyeon Ha,
  • Ayoung Oh,
  • Soo-Yeon Lee,
  • Eun-Jin Choi,
  • Huijeong Choi,
  • Sohee Jo,
  • Jungmin Kim,
  • Sowon Lee,
  • Hyo-Jung Park,
  • Seoyoung Jeon,
  • Sang-In Park,
  • Wookyeom Yang,
  • Jae Hoon Kim,
  • Tae Gyu Choi,
  • Jae-Hwan Nam

摘要

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.

Graphical Abstract