MnCl 2 Nanosheet‐Triggered Mn 2+ Storm Enhances Tumor Immunotherapy Through PANoptosis Induction and cGAS‐STING Activation

ABSTRACT As a vital component of innate immunity, the cGAS‐STING pathway has attracted widespread attention in cancer therapy, among which Mn 2+ has emerged as a promising antitumor agent. Combining cGAS‐STING agonists with chemotherapy or cancer vaccines represents an effective strategy to enhance their therapeutic efficacy. In this study, we construct simple manganese chloride nanosheets (MnCl 2 NSs) that achieve combined effects resembling those of cGAS‐STING activation, chemotherapy, and in situ vaccination without requiring additional drugs or energy input. The synthesized MnCl 2 NSs release high concentrations of Mn 2+ into tumor cells, causing a storm of Mn 2+ . Through the combined effects of osmotic pressure, chemodynamic therapy (CDT), and cGAS‐STING activation, they significantly enhance the cytotoxicity of MnCl 2 and induce DNA damage, thereby achieving chemotherapy‐like combined therapeutic effects. Concurrently, tumor cells undergo PANoptosis, leading to the release of damage‐associated molecular patterns (DAMPs) and tumor antigens, which effectively generate an in situ tumor vaccine, ultimately activating both innate (cGAS‐STING) and adaptive (PANoptosis) immune responses. Our study proposes a novel strategy to synergistically enhance immunotherapy by inducing tumor cell PANoptosis while concurrently activating the cGAS‐STING pathway, offering valuable guidance for the design of immunotherapeutic nanomaterials.