MnCl₂ Nanosheet-Triggered Mn²⁺ 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 Mn²⁺ 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 (MnCl₂ 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 MnCl₂ NSs release high concentrations of Mn²⁺ into tumor cells, causing a storm of Mn²⁺. Through the combined effects of osmotic pressure, chemodynamic therapy (CDT), and cGAS-STING activation, they significantly enhance the cytotoxicity of MnCl₂ 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.

Keywords

cGAS-STING / immunotherapy / Mn²⁺ storm / MnCl₂ nanosheet / PANoptosis

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2026 The Author(s). Aggregate published by SCUT, AIEI, and John Wiley & Sons Australia, Ltd.