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Background Despite the clinical success of cancer immunotherapies using immune checkpoint inhibitors (ICI), only a subset of patients benefits from the treatment while a significant proportion of patients endure toxicity and/or resistance to ICI therapies. The exploration of effective combinations with ICI therapies to augment the anti-tumor efficacy is urgently needed. mRNA cancer vaccine has progressed rapidly in recent years. The combination of cancer vaccine and ICIs has the great potential to improve tumor growth control. Tumor-associated antigens (TAAs) are attractive targets for cancer vaccine development due to their high expression in tumor tissues, but limited expression in normal tissues and their immunogenic property in human.Methods EVM14 is a mRNA-LNP cancer vaccine encoding five TAAs. The in vivo immunogenicity of EVM14 with different dose levels or different immunization schedules were evaluated in multiple mouse strains. Mouse syngeneic tumor models with human TAA expression have been established for anti-tumor activity evaluation of EVM14. The combination therapy of EVM14 and immune checkpoint inhibitors was further tested.Results More than 85% of patients express at least one of the targeted TAAs in multiple cancer types. In vitro experiments demonstrated good expression of five antigens in 293T cells after EVM14 transfection. In vivo immunogenicity studies revealed that EVM14 induced dose-dependent antigen-specific immune response in mice. The efficacy study results demonstrated that EVM14 significantly inhibited tumor growth in multiple tumor models. Dose-dependent anti-tumor activity was observed, in which 10μg/mouse EVM14 led to tumor remission in 5 out of 8 mice. The pharmacodynamics study illustrated that EVM14 significantly induced T cell infiltration into tumor tissues, increased T cell activation and cytotoxic function, decreased Treg population and CTL exhaustion, well correlated with its anti-tumor activity. The exploration with different immunization schedules showed that the earlier the initiation of vaccination, the better the efficacy in tumor growth inhibition. Furthermore, the combination of EVM14 with ICIs (anti-PD1 or anti-CTLA4 antibody) had an overall additive effect on tumor growth inhibition.Conclusions EVM14 significantly stimulated the immune system to elicit antigen-specific immune responses and activated T cells to attack the antigen-expressing tumor cells in mice. The combination of EVM14 with ICIs significantly enhanced the anti-tumor activity. EVM14 is planning to enter Phase I trial in 2025.