Electroacupuncture-Activated Mitochondria-Targeted Polymeric Radicals for cGAS-STING-Activated Immunotherapy.

Area of Science:

• Biomedical Engineering
• Cancer Therapy
• Immunology

Background:

• Free radicals show promise for cancer treatment via oxidative stress.
• Oxygen-dependent radicals face limitations in the tumor microenvironment.
• Novel strategies are needed to overcome these therapeutic barriers.

Purpose of the Study:

• To develop an electroacupuncture-driven strategy integrating organic radical-mediated electrodynamic therapy (EDT) with cGAS-STING pathway-primed immunotherapy.
• To generate oxygen-independent organic radicals for tumor cell eradication.
• To harness mitochondrial damage-induced immune responses for systemic antitumor effects.

Main Methods:

• Utilized mitochondrially engineered viologen derivatives activated by electroacupuncture to generate organic radicals.
• Investigated the mechanism of NADH depletion, mitochondrial electron transport chain disruption, and oxidative stress induction.
• Assessed the activation of the cGAS-STING pathway by released mitochondrial DNA fragments and subsequent immune cell responses.

Main Results:

• Electroacupuncture-induced organic radicals led to direct tumor cell death through oxidative stress and NADH depletion.
• Disruption of mitochondrial architecture released DNA fragments, activating the cGAS-STING pathway.
• This activation promoted type-I interferons, dendritic cell maturation, CD8+ T cell and NK cell proliferation, and tumor infiltration.

Conclusions:

• The integrated strategy demonstrates efficient tumor suppression with minimal toxicity.
• Spatiotemporally controlled organic radical-mediated EDT combined with STING-dependent immunity overcomes microenvironmental barriers.
• This approach offers a promising new avenue for enhancing cancer therapeutic efficacy.