Fig. 2

ROS Generation and Signaling Mechanisms in Tumor Microenvironment Dynamics. a Mitochondrial ROS are predominantly generated through the mitochondrial electrical transport chain (ETC), primarily complex I (Com I) and Com III. Other mitochondrial enzymes, including NADPH oxidase (NOX), can also directly catalyze ROS generation via enzymatic reactions. NOX proteins require various regulatory subunits, includingp40^phox,p47^phox and p67^phox, to exert catalytic effects. These subunits have multiple components in the tumor microenvironment, with differing ROS production and action pathways. b In APC-deficient colorectal cancer cells, ROS production and NF-κB activation in the NOX pathway, triggered by RAC1, promote WNT-driven intestinal stem cell proliferation and cancer development. The mitochondrial ROS pathway can regulate tumor cell proliferation and growth by activating kinases such as JNK and p38 MAPK, as well as ATM in the DNA damage pathway. c Cancer-associated fibroblasts (CAFs) in the tumor microenvironment promote tumor growth and progression and produce ROS through downregulation of mitochondrial electron transport chain, NOX, and antioxidant mechanisms. Oxidative stress can convert fibroblasts into myofibroblasts. ROS mediate TGF-β signaling through various pathways, including redox-dependent accumulation of hypoxia-inducible factor (HIF), stimulating the SDF-1/CXCR4 signaling pathway and activating RhoA-GTPase. Alternatively, ROS can independently stimulate SDF-1, which then causes myofibroblast characteristics in immune cells of TME. d ROS production is mainly by one of the two modalities listed above, depending on the cell type, and is regulated by different stimulating factors and signaling pathways. See the figure for a detailed list of these factors and pathways