| Summary: | Abstract Epstein‐Barr virus (EBV) is associated with various malignancies and infects >90% of the global population. EBV latent proteins are expressed in numerous EBV‐associated cancers and contribute to carcinogenesis, making them critical therapeutic targets for these cancers. Thus, this study aims to develop mRNA‐based therapeutic vaccines that express the T‐cell‐epitope‐rich domain of truncated latent proteins of EBV, including truncatedlatent membrane protein 2A (Trunc‐LMP2A), truncated EBV nuclear antigen 1 (Trunc‐EBNA1), and Trunc‐EBNA3A. The vaccines effectively activate both cellular and humoral immunity in mice and show promising results in suppressing tumor progression and improving survival time in tumor‐bearing mice. Furthermore, it is observed that the truncated forms of the antigens, Trunc‐LMP2A, Trunc‐EBNA1, and Trunc‐EBNA3A, are more effective than full‐length antigens in activating antigen‐specific immune responses. In summary, the findings demonstrate the effectiveness of mRNA‐based therapeutic vaccines targeting the T‐cell‐epitope‐rich domain of EBV latent proteins and providing new treatment options for EBV‐associated cancers.
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