An Immunomodulatory Zinc‐Alum/Ovalbumin Nanovaccine Boosts Cancer Metalloimmunotherapy Through Erythrocyte‐Assisted Cascade Immune Activation

Abstract Cancer therapeutic vaccines are powerful tools for immune system activation and eliciting protective responses against tumors. However, their efficacy has often been hindered by weak and slow immune responses. Here, the authors introduce an immunization strategy employing senescent erythrocytes to facilitate the accumulation of immunomodulatory zinc‐Alum/ovalbumin (ZAlum/OVA) nanovaccines within both the spleen and solid tumors by temporarily saturating liver macrophages. This approach sets the stage for boosted cancer metalloimmunotherapy through a cascade immune activation. The accumulation of ZAlum/OVA nanovaccines in the spleen substantially enhances autophagy‐dependent antigen presentation in dendritic cells, rapidly initiating OVA‐specific T‐cell responses against solid tumors. Concurrently, ZAlum/OVA nanovaccines accumulated in the tumor microenvironment trigger immunogenic cell death, leading to the induction of individualized tumor‐associated antigen‐specific T cell responses and increased T cell infiltration. This erythrocyte‐assisted cascade immune activation using ZAlum/OVA nanovaccines results in rapid and robust antitumor immunity induction, holding great potential for clinical cancer metalloimmunotherapy.