ABSTRACT Current cancer therapeutic vaccines that utilize both CD4 and CD8 T cell neoantigens to stimulate T cell immunity through dendritic cell/macrophage-mediated antigen presentation for their anticancer efficacy. However, despite some promising results in certain cancer types (e.g. melanoma) in preclinical and clinical studies, most of these vaccines have yet to achieve long-term efficacy across different types of cancers. In contrast, the role of B cell immunity in cancer vaccines has been a subject of debate for several decades, and thus therapeutic cancer vaccines have not traditionally been designed to activate B cell immunity. However, recent clinical studies have suggested that B cell-antigen-presentation-mediated B/CD4 T cell crosstalk is crucial for durable anticancer efficacy in immunotherapy. However, most current neoantigen cancer vaccines do not activate B cell-antigen- presentation-mediated B/CD4 T cell crosstalk due to (A) these vaccines, containing only CD4/CD8 T cell epitopes, without B cell epitopes, could not promote B cell-mediated antigen presentation for B/CD4 T cell crosstalk. (B) these vaccine do not have optimized delivery system to enhance B cell epitope binding/crosslink with B cell receptor (BCR) that is required for B cells to uptake antigen for presentation to CD4 T cells. As evidenced by our preliminary data, we hypothesize that VAM-B/CD4 neoantigen vaccine enhances B cell- mediated antigen presentation, activates B/CD4 T cell crosstalk, promotes long-term neoantigen-specific memory B/CD4/CD8 T cell immunity, and achieves durable anticancer efficacy. In addition, our preliminary data also suggest that B/CD4 crosstalk by VAM-B/CD4 is more important for its durable anticancer efficacy than B cell epitope induced antibody production. Therefore, we further hypothesize that a “promiscuous” viral B cell epitope in VAM-B (viral) /CD4 (neoantigen) could promote its binding/crosslink with BCR, which enhances B cell- mediated antigen presentation to activate the required B/CD4 T cell crosstalk for durable anticancer efficacy. This proposal is innovative because VAM-B/CD4 neoantigen vaccine stimulates B cell antigen-presentation- mediated B/CD4 T cell crosstalk and promotes long-term antigen-specific B/CD4/CD8 T cell memory for durable anticancer efficacy. This is distinct from the current T cell cancer vaccine using CD4/CD8 epitope through DC/macrophage mediated-antigen presentation. (B) VAM-B/CD4 uses viral antigen cluster mimicry topography to enhance binding to BCR, promote BCR crosslink, B cell uptake of antigens, and B cell mediated antigen presentation. This is distinct from other nano delivery systems that promote DC/macrophage-mediated uptake and antigen presentation. (C) VAM-B/CD4 vaccine could also use "promiscuous" viral B cell epitopes and cancer neoantigen to promote B/CD4 crosstalk. This project may have significantly positive impact to achieve long-term durable anticancer efficacy in many types of cancers.