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

Area of Science:

• Biochemistry
• Immunology
• Materials Science

Background:

• Targeting mitochondrial DNA (mtDNA) for cancer therapy is an emerging strategy.
• Inducing inflammatory cell death, like pyroptosis, can enhance anti-tumor immune responses.

Purpose of the Study:

• To develop a novel gold(III) complex for targeting mtDNA and inducing pyroptosis.
• To investigate the immunomodulatory effects of this complex in the tumor microenvironment.

Main Methods:

• Synthesis and characterization of a cationic Au(III) Schiff base complex (Au9).
• Assessment of Au9's accumulation in mitochondria and its effects on mtDNA, ROS, ERS, and TrxR activity.
• Evaluation of pyroptosis induction via the caspase-3/GSDME pathway and DAMPs release.
• Analysis of Au9's impact on immune cell populations within the tumor microenvironment.

Main Results:

• Au9 selectively accumulates in mitochondria, damages mtDNA, inhibits TrxR, increases ROS, and induces endoplasmic reticulum stress.
• Au9 effectively triggers pyroptosis and immunogenic cell death (ICD) through the caspase-3/GSDME pathway.
• Au9 promotes dendritic cell maturation and T cell activation (CD4+/CD8+) while decreasing regulatory T cells (Tregs).

Conclusions:

• Au(III) complexes can induce pyroptosis by targeting mtDNA, representing a novel therapeutic avenue.
• This Au(III) complex synergistically enhances anti-tumor immune responses by modulating the tumor immune microenvironment.
• The findings offer innovative strategies for developing metal-based immunotherapeutic agents.