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

Free radicals, with unpaired valence electrons, hold significant potential in cancer treatment by inducing oxidative stress-mediated cellular damage. However, conventional oxygen-dependent radicals encounter significant barriers within the tumor microenvironment. Herein, we propose an electroacupuncture-driven strategy that synergistically integrates organic radical-mediated electrodynamic therapy (EDT) with cGAS-STING pathway-primed immunotherapy. Mitochondrially engineered viologen derivatives can generate stable, oxygen-independent organic radicals under the influence of electroacupuncture. This mechanism leads to a depletion of NADH levels, disrupts the mitochondrial electron transport chain, and induces oxidative stress, resulting in the direct eradication of tumor cells. Concurrently, the accumulation of reactive oxygen species induces the disruption of the mitochondrial cristae architecture, resulting in the release of mitochondrial DNA fragments into the cytoplasm. These fragments subsequently activate the cGAS-STING pathway, thereby promoting expression of type-I interferons, maturation of dendritic cells, proliferation of CD8+ T cells, and natural killer cells, as well as tumor infiltration, ultimately orchestrating a systemic antitumor immune response. This strategy demonstrates highly efficient tumor suppression with minimal toxicity by integrating spatiotemporally precise organic radical-mediated EDT- and STING-dependent immunity, offering a potential strategy to overcome microenvironmental barriers and enhance therapeutic efficacy.