Restoring Tumor Cell Immunogenicity Through Ion‐Assisted p53 mRNA Domestication for Enhanced In Situ Cancer Vaccination Effect

Abstract The efficacy of in situ cancer vaccines (ISCVs) is hindered by the poor immunogenicity of tumor cells. Here, PRIZE, a P53‐repair nanosystem based on a virus‐mimicking nanostructure to deliver p53 mRNA and Zn (II) into tumor cells, domesticating tumor cells by restoring intracellular P53 levels to bolster their immunogenicity, is designed. PRIZE ensures precise delivery to tumor sites, stabilizes p53 mRNA with its biomineralized structure, and extends the half‐life of P53. This research highlights that PRIZE can efficiently repair P53 abnormalities in 4T1 (P53‐deficient) and MC38 (P53‐mutant) cells, subsequently upregulating the expression of major histocompatibility complex (MHC) class I molecules and the surface co‐stimulatory molecule CD80 on tumor cells, enhancing antigen presentation and transforming tumor cells into in situ antigen reservoirs. The co‐delivered photothermal agent (ICG) can trigger immunogenic cell death under laser irradiation, effectively releasing tumor‐associated antigens, and inducing the formation of ISCVs. Importantly, in P53 abnormal tumor mouse models, the induced ISCVs initiate the cancer immune cycle (CIC), demonstrating outstanding tumoricidal immunity and effectively thwarting tumor metastasis and postoperative recurrence, which provides valuable insights for advancing personalized cancer immunotherapy.