Synthetic short mRNA prevents metastasis via innate-adaptive immunity

Hikaru Hayashi, Sayaka Seki, Takeshi Tomita, Masayoshi Kato, Norihiro Ashihara, Tokuhiro Chano, Hideki Sanjo, Miwa Kawade, Chenhui Yan, Hiroki Sakai, Hidenori Tomida, Miyuki Tanaka, Mai Iwaya, Shinsuke Taki, Yozo Nakazawa, Yuji Soejima, Yoshihito Ueno and Sachie Hiratsuka ()
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Hikaru Hayashi: 3-1-1 Asahi
Sayaka Seki: 3-1-1 Asahi
Takeshi Tomita: 3-1-1 Asahi
Masayoshi Kato: 3-1-1 Asahi
Norihiro Ashihara: 3-1-1 Asahi
Tokuhiro Chano: Seta Tsukinowa-cho
Hideki Sanjo: 3-1-1 Asahi
Miwa Kawade: 1-1 Yanagido
Chenhui Yan: 3-1-1 Asahi
Hiroki Sakai: 3-1-1 Asahi
Hidenori Tomida: 3-1-1 Asahi
Miyuki Tanaka: 3-1-1 Asahi
Mai Iwaya: 3-1-1 Asahi
Shinsuke Taki: 3-1-1 Asahi
Yozo Nakazawa: 3-1-1 Asahi
Yuji Soejima: 3-1-1 Asahi
Yoshihito Ueno: 1-1 Yanagido
Sachie Hiratsuka: 3-1-1 Asahi

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Although most cancer deaths are caused by metastasis, there are no effective therapeutic approaches. This study describes the efficacy of a short synthetic mRNA (s-mRNA) designed by the sequence of non-vesicular extracellular IL1β-mRNA found in the pre-metastatic lung of tumor-bearing mice. The administration of s-mRNA inhibits murine lung metastasis by inducing the innate and adaptive immune systems. s-mRNA binds to ZC3H12D, an RNA-binding protein on natural killer cells and cytotoxic T lymphocytes. The ZC3H12D-s-mRNA complex translocated to the nucleus without being involved in translation. This process induces cytolytic activity and cell death in cancer cells without inducing a cytokine storm, and immune cells retain their antitumor activity. Although the antitumor activity of cytotoxic lymphocytes declines as the disease progresses in cancer patients, s-mRNA induces sustained high killing capacities of natural killer cells and cytotoxic T lymphocytes from colon cancer patients. Therefore, s-mRNA could be a breakthrough solution to prevent metastasis.

Date: 2025
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DOI: 10.1038/s41467-025-57123-y

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