Cancer suppresses mitochondrial chaperone activity in macrophages to drive immune evasion

Here we uncover that TNF-receptor associated protein-1 (TRAP1) expression in TAMs is markedly reduced in the TME, a process mediated by the TIM4-AMPK signaling pathway. In addition, TRAP1 deficiency leads to increased activity of mitochondrial electron transport chain complexes and an elevated a-ketoglutarate (a-KG) to succinate ratio. The increase in a-KG facilitate JMJD3-mediated histone demethylation, altering genes expression associated with immunosuppressive activation in macrophages. Overall design: mRNA of naive or YUMM1.7 tumor-conditioned medium (TCM)-treated bone marrow-derived macrophages isolated from TRAP1 WT, TRAP1 KO, JMJD3 WT or JMJD3 conditional KO mice.