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

Cancer immunotherapy is limited by insufficient immunomodulatory efficacy and systemic toxicity. This study reports a giant silver cluster-incorporated polyoxoniobate (PONb), K₆Na₂₁H₃₉{Ag₃₀Cl₄(SeO₃)₄@(SiNb₁₈O₅₄)₆}·96H₂O (1), as a potent immunotherapeutic agent. 1 features a unique core-shell architecture, comprising a silver cluster core [Ag₃₀Cl₄(SeO₃)₄]¹⁸⁺ and a shell of six [SiNb₁₈O₅₄]^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 IC₅₀ 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.