Synthetic Short MRNA Prevents Metastasis Via Innate-adaptive Immunity

Overview

Journal Nat Commun

Specialty Biology

Date 2025 Feb 25

PMID 40000682

Authors

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

Sachie Hiratsuka

Affiliations

Soon will be listed here.

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.

References

Anderson R, Balasas T, Callaghan J, Coombes R, Evans J, Hall J . A framework for the development of effective anti-metastatic agents. Nat Rev Clin Oncol. 2018; 16(3):185-204. PMC: 7136167. DOI: 10.1038/s41571-018-0134-8. View

Gonzalez H, Hagerling C, Werb Z . Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 2018; 32(19-20):1267-1284. PMC: 6169832. DOI: 10.1101/gad.314617.118. View

Fares J, Fares M, Khachfe H, Salhab H, Fares Y . Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther. 2020; 5(1):28. PMC: 7067809. DOI: 10.1038/s41392-020-0134-x. View

Zhao J, Xu L, Sun J, Song M, Wang L, Yuan S . Global trends in incidence, death, burden and risk factors of early-onset cancer from 1990 to 2019. BMJ Oncol. 2025; 2(1):e000049. PMC: 11235000. DOI: 10.1136/bmjonc-2023-000049. View

Lambert A, Pattabiraman D, Weinberg R . Emerging Biological Principles of Metastasis. Cell. 2017; 168(4):670-691. PMC: 5308465. DOI: 10.1016/j.cell.2016.11.037. View

McAllister S, Weinberg R . The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol. 2014; 16(8):717-27. PMC: 6220424. DOI: 10.1038/ncb3015. View

Peinado H, Zhang H, Matei I, Costa-Silva B, Hoshino A, Rodrigues G . Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017; 17(5):302-317. DOI: 10.1038/nrc.2017.6. View

Hiratsuka S, Nakamura K, Iwai S, Murakami M, Itoh T, Kijima H . MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell. 2002; 2(4):289-300. DOI: 10.1016/s1535-6108(02)00153-8. View

Han Y, Tomita T, Kato M, Ashihara N, Higuchi Y, Matoba H . Citrullinated fibrinogen-SAAs complex causes vascular metastagenesis. Nat Commun. 2023; 14(1):4960. PMC: 10449786. DOI: 10.1038/s41467-023-40371-1. View

Granot Z, Henke E, Comen E, King T, Norton L, Benezra R . Tumor entrained neutrophils inhibit seeding in the premetastatic lung. Cancer Cell. 2011; 20(3):300-14. PMC: 3172582. DOI: 10.1016/j.ccr.2011.08.012. View

10.

Correia A . Locally sourced: site-specific immune barriers to metastasis. Nat Rev Immunol. 2023; 23(8):522-538. PMC: 9904275. DOI: 10.1038/s41577-023-00836-2. View

11.

Algarra I, Garrido F, Garcia-Lora A . MHC heterogeneity and response of metastases to immunotherapy. Cancer Metastasis Rev. 2021; 40(2):501-517. DOI: 10.1007/s10555-021-09964-4. View

12.

Shaver K, Croom-Perez T, Copik A . Natural Killer Cells: The Linchpin for Successful Cancer Immunotherapy. Front Immunol. 2021; 12:679117. PMC: 8115550. DOI: 10.3389/fimmu.2021.679117. View

13.

Sun L, Kees T, Almeida A, Liu B, He X, Ng D . Activating a collaborative innate-adaptive immune response to control metastasis. Cancer Cell. 2021; 39(10):1361-1374.e9. PMC: 8981964. DOI: 10.1016/j.ccell.2021.08.005. View

14.

Tomita T, Kato M, Mishima T, Matsunaga Y, Sanjo H, Ito K . Extracellular mRNA transported to the nucleus exerts translation-independent function. Nat Commun. 2021; 12(1):3655. PMC: 8208975. DOI: 10.1038/s41467-021-23969-1. View

15.

Kaplan R, Riba R, Zacharoulis S, Bramley A, Vincent L, Costa C . VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005; 438(7069):820-7. PMC: 2945882. DOI: 10.1038/nature04186. View

16.

Maeda K, Akira S . Regulation of mRNA stability by CCCH-type zinc-finger proteins in immune cells. Int Immunol. 2017; 29(4):149-155. PMC: 5890888. DOI: 10.1093/intimm/dxx015. View

17.

Kano T, Katsuragi Y, Maeda Y, Ueno Y . Synthesis and properties of 4'-C-aminoalkyl-2'-fluoro-modified RNA oligomers. Bioorg Med Chem. 2018; 26(15):4574-4582. DOI: 10.1016/j.bmc.2018.08.001. View

18.

Inoue H, Hayase Y, Imura A, Iwai S, Miura K, Ohtsuka E . Synthesis and hybridization studies on two complementary nona(2'-O-methyl)ribonucleotides. Nucleic Acids Res. 1987; 15(15):6131-48. PMC: 306073. DOI: 10.1093/nar/15.15.6131. View

19.

Eckstein F . Phosphorothioates, essential components of therapeutic oligonucleotides. Nucleic Acid Ther. 2014; 24(6):374-87. DOI: 10.1089/nat.2014.0506. View