The recent FDA approval of several immunotherapeutic drugs, such as checkpoint blockade, have solidified immunotherapy as a viable means for treating several types of cancer. A major drawback to many of these approved therapies, however, is that they often induce immune responses that cross react with normal healthy cells, resulting in autoimmunity. Personalized cancer vaccines targeting tumor-specific neoantigens that arise from somatic missense mutations represent a promising modality that can mitigate this outcome, but uncertainties remain as to their most effective design. To better understand the compositional requirements of efficacious neoantigen vaccines, we investigated the mechanism of several therapeutic synthetic long peptide (SLP) vaccines targeting mouse-tumor neoantigens. This led to the identification of three generalizable principles governing the effectiveness of neoantigen-targeting SLPs: (1) neoantigen-reactive CD8+ T cells drive direct antitumor benefits; therefore, SLPs must contain a MHC I-restricted neoepitope; (2) to induce potent neoantigen-reactive CD8+ T-cell responses, SLPs must mediate CD40L interactions (i.e. T-cell “help” signal); and (3) CD40L interactions are conferred by a SLP only when a “helper” epitope is physically linked to a MHC I-restricted neoepitope. These findings prompted us to test rationally-designed neoantigen vaccines comprised of a MHC I-restricted neoepitope linked to the universal “helper” epitope from tetanus toxin, P30. Remarkably, this vaccine design was able to unveil immune and antitumor effects to neoantigens that were otherwise poorly immunogenic. These data are encouraging because they demonstrate a clinically tractable approach with the potential to increase the therapeutic breadth of neoantigen vaccines for a variety of tumor types.