Au(III) Complexes as Pyroptosis Inducers by Targeting Mitochondrial DNA for Tumor Immunity

Abstract

ABSTRACT Targeting mitochondrial DNA (mtDNA) to induce a highly inflammatory form of cell death, such as pyroptosis, represents a promising yet underexplored therapeutic strategy. In this study, we report a novel cationic Au(III) Schiff base complex ( Au9 ) that selectively accumulates in mitochondria, targets mtDNA, and induces mtDNA damage. Additionally, Au9 inhibits thioredoxin reductase (TrxR) activity, elevates reactive oxygen species (ROS) levels, and triggers endoplasmic reticulum stress (ERS). These combined effects activate the caspase‐3/gasdermin E (GSDME) pathway, leading to pyroptosis. This process is accompanied by the release of damage‐associated molecular patterns (DAMPs), significantly enhancing immunogenic cell death (ICD). Further investigations indicate that Au9 effectively modulates the tumor immune microenvironment by promoting dendritic cells (DCs) maturation and CD4 + /CD8 + T cells activation while reducing the proportion of immunosuppressive regulatory T cells (Tregs). This study provides the first evidence that Au(III) complexes can induce pyroptosis by targeting mtDNA and synergistically enhance antitumor immune responses, offering innovative strategies for developing novel metal‐based immunotherapeutic agents.