Context-dependent NRF2 signaling in cancer: mechanisms and precision modulation.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a central transcription factor in the cellular antioxidant stress response, whose activity exhibits marked context-dependence. Under normal physiological conditions and in precancerous lesions, timely and moderate activation of the NRF2 pathway establishes a multi-layered, synergistic cellular defense network. Through mechanisms including efficient detoxification of exogenous carcinogens, clearance of excess reactive oxygen species (ROS), suppression of chronic inflammation, maintenance of genomic stability, regulation of autophagic homeostasis, and promotion of immune surveillance to eliminate precancerous cells, NRF2 exerts potent chemopreventive effects, thereby preventing malignant transformation. In established malignancies, however, constitutive activation of the NRF2 pathway—driven by mutations in KEAP1/NRF2 or persistent oncogenic signaling—fundamentally reverses its role. Under these conditions, NRF2 becomes a central hub that promotes tumor progression and therapy resistance by remodeling redox homeostasis to sustain low ROS levels favorable for proliferation, reprogramming metabolism to support biosynthetic demands, upregulating multidrug resistance-associated proteins, and shaping an immunosuppressive tumor microenvironment. This review examines the molecular basis of the dual roles of NRF2 at different stages of carcinogenesis and summarizes the distinct biological effects of natural and synthetic modulators of this pathway.