A High‐Nuclear Silver Cluster Incorporated Polyoxoniobate Boosts Antitumor Immunity With Low Systemic Toxicity

ABSTRACT Cancer immunotherapy is limited by insufficient immunomodulatory efficacy and systemic toxicity. This study reports a giant silver cluster‐incorporated polyoxoniobate (PONb), K 6 Na 21 H 39 {Ag 30 Cl 4 (SeO 3 ) 4 @(SiNb 18 O 54 ) 6 }·96H 2 O ( 1 ), as a potent immunotherapeutic agent. 1 features a unique core‐shell architecture, comprising a silver cluster core [Ag 30 Cl 4 (SeO 3 ) 4 ] 18+ and a shell of six [SiNb 18 O 54 ] 14− polyanions. Notably, 1 contains the largest silver cluster (30 Ag + ) in a molecular PONb with solubility and biocompatibility under physiological conditions to date. In vitro, 1 exhibits potent cytotoxicity against mouse colorectal carcinoma cells with an IC 50 of 0.11 µM, triggering immunogenic cell death (ICD). Additionally, it induces polarization of macrophages to the antitumor M1‐phenotype. In vivo, it outperforms doxorubicin (DOX) in suppressing tumor growth, with 1 achieving 90.63% tumor inhibition at 5 mg/kg (0.23 µmol/kg). Unlike DOX‐induced immunosuppression and hepatic toxicity, 1 robustly activates antitumor immune response via an ROS‐dependent mechanism by promoting T cell priming in the tumor‐draining lymph node and effector T cell infiltration into tumors, without impairing organ functions. Moreover, 1 converts tumor‐associated macrophages (TAMs) from the protumorogenic M2‐phenotype to the antitumor M1‐phenotype, further reprogramming the immune microenvironment in tumor tissues. This study validates PONbs as a promising class of immunotherapeutics, bridging structural innovation in inorganic chemistry with improved cancer immunotherapy.