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A recently synthesized mitochondria\u2010targeted atovaquone increased mitochondrial accumulation and antitumor activity in vitro. Using an in situ vaccination approach, local injection of mitochondria\u2010targeted atovaquone into primary tumors triggered potent T cell immune responses locally and in distant tumor sites. Mitochondria\u2010targeted atovaquone treatment led to significant reductions of both granulocytic myeloid\u2010derived suppressor cells and regulatory T cells in the tumor microenvironment. Mitochondria\u2010targeted atovaquone treatment blocks the expression of genes involved in oxidative phosphorylation and glycolysis in granulocytic\u2010myeloid\u2010derived suppressor cells and regulatory T cells, which may lead to death of granulocytic\u2010myeloid\u2010derived suppressor cells and regulatory T cells. Mitochondria\u2010targeted atovaquone inhibits expression of genes for mitochondrial complex components, oxidative phosphorylation, and glycolysis in both granulocytic\u2010myeloid\u2010derived suppressor cells and regulatory T cells. The resulting decreases in intratumoral granulocytic\u2010myeloid\u2010derived suppressor cells and regulatory T cells could facilitate the observed increase in tumor\u2010infiltrating CD4<jats:sup>+<\/jats:sup> T cells. Mitochondria\u2010targeted atovaquone also improves the anti\u2010tumor activity of PD\u20101 blockade immunotherapy. The results implicate granulocytic\u2010myeloid\u2010derived suppressor cells and regulatory T cells as novel targets of mitochondria\u2010targeted atovaquone that facilitate its antitumor efficacy.<\/jats:p>","DOI":"10.1002\/advs.202101267","type":"journal-article","created":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T04:39:48Z","timestamp":1646368788000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria\u2010Targeted Atovaquone"],"prefix":"10.1002","volume":"9","author":[{"given":"Mofei","family":"Huang","sequence":"first","affiliation":[{"name":"Center for Cancer Prevention Houston Methodist Research Institute  6670 Bertner Ave Houston TX 77030 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghai","family":"Xiong","sequence":"additional","affiliation":[{"name":"Center for Cancer Prevention Houston 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