Fu Jiayan, Wu Shuangqi, Bao Nengcheng, Wu Lili, Qu Huiru, Wang Zhechao, Dong Haiyang, Wu Jian, Jin Yongfeng
National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
MOE Laboratory of Biosystems Homeostasis & Protection, Innovation Center for Cell Signaling Network, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Adv Sci (Weinh). 2025 Feb;12(8):e2401287. doi: 10.1002/advs.202401287. Epub 2025 Jan 6.
Personalized neoantigen cancer mRNA vaccines are promising candidates for precision medicine. However, the difficulty of identifying neoantigens heavily hinders their broad applicability. This study developed a universal strategy of anti-tumor mRNA vaccine by harnessing "off-the-shelf" immunity to known antigens. First, the model antigen ovalbumin (OVA) is used for mRNA vaccine design. In vitro test indicated that this mRNA vaccine reprogrammed tumor cells that can be recognized and killed by OVA-specific cytotoxic T lymphocytes (CTLs). In situ mRNA vaccine notably inhibited tumor growth across three subcutaneous solid tumor models in mice. Further single-cell sequencing analyses revealed that mRNA vaccination act to reshape the immunosuppressive tumor microenvironment (TME) toward more proinflammatory characteristics. Strikingly, this framework of mRNA-based strategy can be applied to two clinical pathogen antigens, hepatitis B surface antigen (HBsAg), and SARS-CoV-2 spike receptor-binding domain (SRBD). Interestingly, the mRNA-based strategy largely recapitulated the scenario of spontaneous cancer regression following pathogen infection or vaccination. Collectively, this study provides not only proof of concept for universal anti-tumor mRNA therapy, but also mechanistic insights in echoing the long-standing puzzle of spontaneous cancer regression.
个性化新抗原癌症mRNA疫苗是精准医学中很有前景的候选方案。然而，新抗原识别的困难严重阻碍了它们的广泛应用。本研究通过利用对已知抗原的“现成”免疫，开发了一种通用的抗肿瘤mRNA疫苗策略。首先，将模型抗原卵清蛋白（OVA）用于mRNA疫苗设计。体外试验表明，这种mRNA疫苗可重编程肿瘤细胞，使其能被OVA特异性细胞毒性T淋巴细胞（CTL）识别并杀死。原位mRNA疫苗在小鼠的三种皮下实体瘤模型中显著抑制了肿瘤生长。进一步的单细胞测序分析表明，mRNA疫苗接种可将免疫抑制性肿瘤微环境（TME）重塑为更具促炎特征的环境。引人注目的是，这种基于mRNA的策略框架可应用于两种临床病原体抗原，即乙型肝炎表面抗原（HBsAg）和严重急性呼吸综合征冠状病毒2刺突受体结合域（SRBD）。有趣的是，基于mRNA的策略在很大程度上重现了病原体感染或疫苗接种后自发癌症消退的情况。总体而言，本研究不仅为通用抗肿瘤mRNA治疗提供了概念验证，还为回应长期存在的自发癌症消退之谜提供了机制性见解。
