Targeted Reprogramming of Tumor Cells by Digoxin‐Loaded Immunogenic Nanoparticles Enhances Immunity Against Disseminated Tumor Cells

To potentiate the in situ vaccine effect of radiotherapy (RT), an “inflamed‐cell‐as‐vaccine” strategy is proposed. Specifically, a biomimetic, tumor‐targeting nanoparticle (rVAR2‐M‐NP) carrying a Digoxin‐Ovalbumin (Dig‐Ova) complex is engineered as its core payload. This nanoparticle‐induced gentle immunogenic cell death (ICD) stress promotes self‐inflammation in tumor cells without causing direct cytotoxicity. Compared to treatment with Digoxin alone, rVAR2‐M‐NPs significantly enhance the expression of immunogenic cytokines in tumor cells, effectively suppress hypoxia inducible factor‐1α (HIF‐1α) expression, and render tumor cells more susceptible to RT without increasing reactive oxygen species (ROS) levels. In both in vitro and in vivo experiments, treatment with rVAR2‐M‐NPs transform tumor cells into an activated, “inflamed” state, markedly amplifying their immunogenic potential. When integrated with conventional cancer therapies — including surgery, γ‐ray irradiation, and anti‐PD‐1 immunotherapy — the rVAR2‐M‐NP treatment robustly inhibits primary tumor growth and metastasis in orthotopic 4T1 tumors and significantly improves survival outcomes without notable side effects. Given the increasing interest in leveraging RT‐induced in situ vaccination to stimulate systemic antitumor immunity against distant, disseminated, untreated tumors, the findings demonstrate that nanoparticle‐delivered immunogens capable of inducing controlled ICD stress can effectively convert tumor cells into a potent cellular nanovaccine, substantially enhancing the therapeutic efficacy of RT‐based immunotherapy.