Lipid nanoparticle (LNP)-mRNA-based tumor immunotherapy needs to address challenges such as low efficacy of mRNA delivery, targeted protein expression, and compromised innate immunogenicity. Here, we screen a panel of 16 cyclic acetal-based ionizable lipid nanoparticles by in vitro and in vivo assays to develop a more effective and safer system specifically for tumor immunotherapy and mRNA delivery. Furthermore, by incorporating a cyclic acetal-based adjuvant lipid YK-TLR-001, two optimized cyclic acetal-based LNP formulations (YK-712 and YK-716) are demonstrated to enhance mRNA expression in the spleens and to induce exceptional maturation of antigen-presenting cells (APCs) and to promote antigen presentation. Moreover, animal studies treated with these formulations show activated cellular immunogenicity in healthy mice and inhibited tumor growth in the B16F10 melanoma model. Thus, the cyclic acetal-based LNPs with YK-TLR-001 present a promising direction in the design of mRNA vectors for the advancement of mRNA tumor immunotherapy.