Irradiation-based development of tumor vaccines: Mechanistic insights and translational exploration

Irradiation-based cancer vaccines represent a promising immunotherapeutic strategy, primarily comprising in vitro-irradiation-prepared cancer vaccine (ICV) and in situ-irradiation-induced cancer vaccine (ISCV). ICV leverages the complete antigenic repertoire of irradiation-inactivated tumor cells to activate polyclonal T-cell responses via antigen-presenting cells (APCs), thereby overcoming tumor heterogeneity. In contrast, ISCV directly transforms the tumor into an endogenous "antigen factory" through focal irradiation-induced immunogenic cell death, which releases tumor antigens and danger signals to initiate systemic anti-tumor immunity and the abscopal effect. Despite their potential, challenges such as optimal dosing, the immunosuppressive tumor microenvironment, and personalized regimen design remain. Future clinical translation is poised to leverage combination strategies with immune checkpoint inhibitors, cytokines, or nanotechnology-based delivery systems to enhance therapeutic efficacy. Here, we review the action and effects of irradiation, the mechanisms underlying antigen presentation and immune activation of the two vaccines, summarize the progress of relevant clinical trials, and provide an outlook on future development directions-with the aim of offering references for the development and clinical translation of new vaccines. Despite their fundamental divergence in antigen sourcing (exogenous and endogenous origins), both modalities act through APC-mediated adaptive immune responses. Distinct translational obstacles exist for each platform, which requires biomarker-guided patient selection and ethically justified combination therapies to realize safe and equitable clinical translation.