Synchronous effects of targeted mitochondrial complex I inhibitors on tumor and immune cells abrogate melanoma progression

作者：Mahmoud AbuEid, Donna McAllister, Laura McOlash, Megan Cleland Harwig, Gang Cheng, Donovan Drouillard, Kathleen A. Boyle, Micaël Hardy, Jacek Zielonka, Bryon D. Johnson, R. Blake Hill, Balaraman Kalyanaraman, Michael B. Dwinell · 发表于：iScience · 年份：2021 · DOI：10.1016/j.isci.2021.102653 · 被引用次数：26 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis

Metabolic heterogeneity within the tumor microenvironment promotes cancer cell growth and immune suppression. We determined the impact of mitochondria-targeted complex I inhibitors (Mito-CI) in melanoma. Mito-CI decreased mitochondria complex I oxygen consumption, Akt-FOXO signaling, blocked cell cycle progression, melanoma cell proliferation and tumor progression in an immune competent model system. Immune depletion revealed roles for T cells in the antitumor effects of Mito-CI. While Mito-CI preferentially accumulated within and halted tumor cell proliferation, it also elevated infiltration of activated effector T cells and decreased myeloid-derived suppressor cells (MDSC) as well as tumor-associated macrophages (TAM) in melanoma tumors in vivo . Anti-proliferative doses of Mito-CI inhibited differentiation, viability, and the suppressive function of bone marrow-derived MDSC and increased proliferation-independent activation of T cells. These data indicate that targeted inhibition of complex I has synchronous effects that cumulatively inhibits melanoma growth and promotes immune remodeling.