Fig. 1

Scheme of mitochondrial ROS stress promotes cell survival and inflammation that causes an immunosuppressive tumor microenvironment (TME) to induce tumorigenesis. Mitochondria are the major cellular source of ROS generation. Mitochondrial ROS (mtROS) are mainly produced by mitochondrial aerobic respiration or as a byproduct of the activity of metabolic enzymes. Chaperone Lon is the major one of mitochondrial protein quality control system. Lon binds with NDFUS8 in the Complex I of electron transport chain and with PYCR1 reductase to up-regulate mtROS generation to promote cell proliferation and inflammation. Mitochondrial chaperone complex of HSP60-mtHSP70-Lon sequesters p53 in mitochondria matrix and stabilizes with NCLX (Na⁺/ Ca²⁺ exchanger) to restrain apoptosis and increase the cisplatin resistance under ROS stress. In addition, mtROS cause the oxidative damage on mtDNA and induce IFN signaling that upregulates PD-L1 expression to inhibit T-cell activation. Under ROS stress, cancer cells to secrete NF-κB-dependent inflammatory cytokines ( IL-6, IFN-γ, TGFβ, VEGF, IL-4, and IL-10) to cause the immunosuppressive state of macrophages, dendritic cells (DC), and T cells (Treg). Upregulation of Lon by ROS and hypoxia also induces the secretion of extracellular vehicles (EVs) that carry mtDNA and PD-L1. mtROS-induced EVs further induce the production of IFN and IL-6 from macrophages, which attenuates T-cell immunity in the TME. Macrophage-induced ROS leads to the accumulation of Treg and regDC cells. In short, mtROS cause an immunosuppressive TME to promote immunoescape, survival, and EMT/metastasis of cancer cells