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<p>Immunotherapy has limited success in pancreatic ductal adenocarcinoma (PDAC) due to an immune exclusive tumor microenvironment (TME) that lacks many cytokines necessary for Natural Killer (NK) and T cell responses. Here, we design multiplexed mRNAs encoding interleukins, chemokines, and interferons as a safe and effective cytokine therapy for PDAC. Intratumoral injection of IL-12, IL-18, CCL5, CXCL10, and IFNβ mRNAs achieves robust yet transient cytokine expression, leading to NK and CD8<sup>+</sup> T cell activation and reduced tumor growth and fibrosis in PDAC transplant mouse models. Combining cytokine with tumor antigen mRNAs enhances dendritic cell antigen presentation and CD8<sup>+</sup> T cell priming locally and systemically that prolongs animal survival after a single dose. Remarkably, nanoparticle encapsulation of the cytokine/antigen mRNA cocktail allows systemic administration and local delivery to autochthonous PDAC tumors in mice, culminating in curative responses in 50% of animals and antigen-reactive T cell persistence. These results suggest that multiplexed mRNA approaches to deliver cytokines and antigens generally absent in the TME could pave the way for effective immunotherapy in PDAC.</p>

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Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Chaitanya N. Parikh,
  • Kelly D. DeMarco,
  • Nikita Bhalerao,
  • Hadiya K. Giwa,
  • Griffin I. Kane,
  • Ronnie W. Dinnell,
  • Boyang Ma,
  • Haruka Mori,
  • Meghan L. Brassil,
  • Katherine C. Murphy,
  • Zhen Zhao,
  • Calvin Johnson,
  • Shriram Ramani,
  • Lin Zhou,
  • Loretah Chibaya,
  • Youwei Qiao,
  • Kai Hu,
  • Lihua Julie Zhu,
  • Brian C. Lewis,
  • Wen Xue,
  • Jason R. Pitarresi,
  • Prabhani U. Atukorale,
  • Marcus Ruscetti

摘要

Immunotherapy has limited success in pancreatic ductal adenocarcinoma (PDAC) due to an immune exclusive tumor microenvironment (TME) that lacks many cytokines necessary for Natural Killer (NK) and T cell responses. Here, we design multiplexed mRNAs encoding interleukins, chemokines, and interferons as a safe and effective cytokine therapy for PDAC. Intratumoral injection of IL-12, IL-18, CCL5, CXCL10, and IFNβ mRNAs achieves robust yet transient cytokine expression, leading to NK and CD8+ T cell activation and reduced tumor growth and fibrosis in PDAC transplant mouse models. Combining cytokine with tumor antigen mRNAs enhances dendritic cell antigen presentation and CD8+ T cell priming locally and systemically that prolongs animal survival after a single dose. Remarkably, nanoparticle encapsulation of the cytokine/antigen mRNA cocktail allows systemic administration and local delivery to autochthonous PDAC tumors in mice, culminating in curative responses in 50% of animals and antigen-reactive T cell persistence. These results suggest that multiplexed mRNA approaches to deliver cytokines and antigens generally absent in the TME could pave the way for effective immunotherapy in PDAC.