In vivo engineering tumor cells to a universal "all-in-one" cancer vaccine with full antigen spectrum

Cancer vaccines offer a promising strategy to initiate de novo T cell responses or enhance existing ones, either functioning independently or synergizing with T cell-modulating therapeutics to reduce tumor burden. The clinical development of cancer vaccines faces challenges such as limited antigen coverage, insufficient antigen presentation, immune suppressive microenvironment, and the availability of personalized vaccines. In this study, we developed a universal "all-in-one" cancer cell-derived vaccine (UniCVac) with comprehensive antigen spectrum coverage by programming tumor cells into antigen-presenting cells (APCs) through the codelivery of CIITA, NLRC5, CD80, and IL-2. This reprogramming mimics the professional APC phenotype, providing simultaneous HLA-I and HLA-II antigen presentation, costimulation, and T cell proliferation signals. These tumor-derived UniCVac can directly activate both CD4⁺ and CD8⁺ T cells in vitro, independent of APCs. In addition, their costimulation and T cell growth-stimulating capabilities result in superior CD4⁺ and CD8⁺ T cell activation and proliferation comparable to traditional APCs, with enhanced PI3K-AKT pathways activation. Single-cell transcriptome analysis confirmed the similarity in cellular subtypes between UniCVac-activated and traditional APC-activated T cells. In mouse models, the UniCVac vaccination reprogramed the tumor microenvironment from immunosuppressive to immune-permissive, induced robust CD4⁺ and CD8⁺ T cell expansion in both preventive and therapeutic tumor models, and achieved complete tumor regression in vivo. Our approach provides a platform for the development of universal cancer vaccines with full antigen spectrum coverage and the ability to directly activate both CD4⁺ and CD8⁺ T cells, offering potential combinatorial opportunities with existing T cell-based immunotherapies against cancer.