Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria‐Targeted Atovaquone

Atovaquone, an FDA‐approved drug for malaria, is known to inhibit mitochondrial electron transport. A recently synthesized mitochondria‐targeted atovaquone increased mitochondrial accumulation and antitumor activity in vitro. Using an in situ vaccination approach, local injection of mitochondria‐targeted atovaquone into primary tumors triggered potent T cell immune responses locally and in distant tumor sites. Mitochondria‐targeted atovaquone treatment led to significant reductions of both granulocytic myeloid‐derived suppressor cells and regulatory T cells in the tumor microenvironment. Mitochondria‐targeted atovaquone treatment blocks the expression of genes involved in oxidative phosphorylation and glycolysis in granulocytic‐myeloid‐derived suppressor cells and regulatory T cells, which may lead to death of granulocytic‐myeloid‐derived suppressor cells and regulatory T cells. Mitochondria‐targeted atovaquone inhibits expression of genes for mitochondrial complex components, oxidative phosphorylation, and glycolysis in both granulocytic‐myeloid‐derived suppressor cells and regulatory T cells. The resulting decreases in intratumoral granulocytic‐myeloid‐derived suppressor cells and regulatory T cells could facilitate the observed increase in tumor‐infiltrating CD4(+) T cells. Mitochondria‐targeted atovaquone also improves the anti‐tumor activity of PD‐1 blockade immunotherapy. The results implicate granulocytic‐myeloid‐derived suppressor cells and regulatory T cells as novel targets of mitochondria‐targeted atovaquone that facilitate its antitumor efficacy.