A Universal Therapeutic Vaccine Leveraging Autologous Pre‐Existing Immunity to Eliminate in Situ Uniformly Engineered Heterogeneous Tumor Cells

Abstract Tumor vaccines that activate the autologous immune system to eliminate tumor cells represent a promising approach in cancer immunotherapy. However, challenges such as tumor heterogeneity, limited antigen selection, insufficient antigen presentation, and the slow onset of de novo immune responses have resulted in poor universality and suboptimal response rates. In contrast, pathogen‐specific pre‐existing immunity acquired through infection or vaccination, can rapidly generate a more potent and enduring immune response upon re‐encounter with the same antigen. Here, an adeno‐associated virus (AAV)‐based therapeutic vaccine capable of genetically modifying diverse tumor cells to uniformly overexpress and efficiently present the highly immunogenic transmembrane SARS‐CoV‐2 receptor binding domain (RBD), and to release RBD‐enveloped virus‐like particles, which awaken and enhance the RBD‐specific pre‐existing immunity, leading to significant tumor remission, is engineered. Mechanistically, this therapeutic vaccine leverages the robust RBD‐specific pre‐existing immunity and heightened antibody‐mediated phagocytosis to eliminate engineered tumor cells while inducing antigen spreading, thereby provoking a more diverse tumor‐specific cellular immune responses. Notably, widespread administration of vaccines against various pathogens has provided a versatile pool of pre‐existing immunity that can be redirected to eradicate tumors. These findings offer a novel perspective on overcoming the limitations posed by tumor heterogeneity and personalized medicine.