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

International audienceMetabolic heterogeneity within the tumor microenvironment promotes cancercell 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 cycleprogression, melanoma cell proliferation and tumor progression in an immunecompetent model system. Immune depletion revealed roles for T cells in the antitumor effects of Mito-CI. While Mito-CI preferentially accumulated within andhalted tumor cell proliferation, it also elevated infiltration of activated effectorT 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-independentactivation of T cells. These data indicate that targeted inhibition of complex Ihas synchronous effects that cumulatively inhibits melanoma growth and promotes immune remodeling