Hayashi Hikaru, Seki Sayaka, Tomita Takeshi, Kato Masayoshi, Ashihara Norihiro, Chano Tokuhiro, Sanjo Hideki, Kawade Miwa, Yan Chenhui, Sakai Hiroki, Tomida Hidenori, Tanaka Miyuki, Iwaya Mai, Taki Shinsuke, Nakazawa Yozo, Soejima Yuji, Ueno Yoshihito, Hiratsuka Sachie
Department of Biochemistry and Molecular Biology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan.
Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, Japan.
Nat Commun. 2025 Feb 25;16(1):1925. doi: 10.1038/s41467-025-57123-y.
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.
尽管大多数癌症死亡是由转移引起的，但目前尚无有效的治疗方法。本研究描述了一种短链合成信使核糖核酸（s-mRNA）的疗效，该s-mRNA是根据在荷瘤小鼠肺转移前非囊泡细胞外白细胞介素1β信使核糖核酸（IL1β-mRNA）序列设计的。s-mRNA的给药通过诱导先天性和适应性免疫系统来抑制小鼠肺转移。s-mRNA与自然杀伤细胞和细胞毒性T淋巴细胞上的一种RNA结合蛋白ZC3H12D结合。ZC3H12D-s-mRNA复合物无需参与翻译即可转运至细胞核。这一过程在不引发细胞因子风暴的情况下诱导癌细胞的溶细胞活性和细胞死亡，并且免疫细胞保留其抗肿瘤活性。尽管在癌症患者中，随着疾病进展细胞毒性淋巴细胞的抗肿瘤活性会下降，但s-mRNA可诱导结肠癌患者的自然杀伤细胞和细胞毒性T淋巴细胞持续保持高杀伤能力。因此，s-mRNA可能是预防转移的突破性解决方案。
