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However, the difficulty of identifying neoantigens heavily hinders their broad applicability. This study developed a universal strategy of anti\u2010tumor mRNA vaccine by harnessing \u201coff\u2010the\u2010shelf\u201d 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\u2010specific cytotoxic T lymphocytes (CTLs). In situ mRNA vaccine notably inhibited tumor growth across three subcutaneous solid tumor models in mice. Further single\u2010cell sequencing analyses revealed that mRNA vaccination act to reshape the immunosuppressive tumor microenvironment (TME) toward more proinflammatory characteristics. Strikingly, this framework of mRNA\u2010based strategy can be applied to two clinical pathogen antigens, hepatitis B surface antigen (HBsAg), and SARS\u2010CoV\u20102 spike receptor\u2010binding domain (SRBD). 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