Mitochondrial oxidative stress in the tumor microenvironment and cancer immunoescape: foe or friend?

Abstract

The major concept of "oxidative stress" is an excess elevated level of reactive oxygen species (ROS) which are generated from vigorous metabolism and consumption of oxygen. The precise harmonization of oxidative stresses between mitochondria and other organelles in the cell is absolutely vital to cell survival. Under oxidative stress, ROS produced from mitochondria and are the major mediator for tumorigenesis in different aspects, such as proliferation, migration/invasion, angiogenesis, inflammation, and immunoescape to allow cancer cells to adapt to the rigorous environment. Accordingly, the dynamic balance of oxidative stresses not only orchestrate complex cell signaling events in cancer cells but also affect other components in the tumor microenvironment (TME). Immune cells, such as M2 macrophages, dendritic cells, and T cells are the major components of the immunosuppressive TME from the ROS-induced inflammation. Based on this notion, numerous strategies to mitigate oxidative stresses in tumors have been tested for cancer prevention or therapies; however, these manipulations are devised from different sources and mechanisms without established effectiveness. Herein, we integrate current progress regarding the impact of mitochondrial ROS in the TME, not only in cancer cells but also in immune cells, and discuss the combination of emerging ROS-modulating strategies with immunotherapies to achieve antitumor effects.

Keywords: Cisplatin resistance; Combination cancer immunotherapy; Hypoxia; Immunoescape; Inflammation; Lon protease (LonP1); Mitochondrial chaperone; Mitochondrial reactive oxygen species (mtROS); Tumor microenvironment.

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