NRF2-driven redox metabolism takes center stage in cancer metabolism from an outside-in perspective.

Cancer development is a process of somatic clonal evolution. Darwinian principles of evolution emphasize the interaction between heritable individual variability and selective pressure from the environment. However, the current prevailing concept of cancer evolution mostly focuses on the alterations of genes, signaling, and metabolism inside cells, which underestimates the impact of environmental pressure in selecting the adapted cells. Recently, unsuccessful outcomes and many concerns raised in targeting those alterations inside cells have cast doubt on the current "cell-centric" paradigm of cancer formation, which necessitates a paradigm shift to an outside-in direction that considers environmental changes as a driver in determining the characteristics of selected cells. In the tumor microenvironment, reactive oxygen species (ROS) are one of the most abundant chemical constituents generated by inflammatory and hypoxic conditions. Because of their cytotoxicity when present at high levels, ROS should be the pressure that selects cells with a high capacity for ROS metabolism and antioxidant defense, both of which are referred to as redox metabolism. Cancer genome analyses have found that nuclear factor E2-related factor 2 (NRF2), which plays an indispensable role in redox metabolism, is frequently activated in many types of cancer, particularly lung cancer. This suggests that an ROS-rich microenvironment drives the selection, survival, and growth of cells with high NRF2 activity. Thus, NRF2-driven redox metabolism should be the most crucial part of cancer metabolism, proposing NRF2 inhibitor as an attractive therapeutic target for cancer.