Background <p>The development and clinical success of KRAS^G12C inhibitors was a landmark achievement in anti-cancer drug development, as oncogenic KRAS had long been considered an intractable therapeutic target. Patients with <i>KRAS</i> mutant lung cancers frequently present with co-mutations in the KEAP1-NRF2 pathway, and because genetic activation of NRF2 results in resistance to all current anti-cancer therapies, we were motivated to explore how aberrant activation of NRF2 impacts the clinical response to KRAS^G12C inhibitors.</p> Methods <p>A broad range of techniques, including genetic knockouts, scRNA-seq and surface plasmon resonance, were used to determine the effect of KRAS^G12C drugs on NRF2.</p> Results <p>At physiologically-relevant concentrations, both of the clinically-approved KRAS^G12C inhibitors Sotorasib and Adagrasib also function as inducers of NRF2. Mechanistically, the same cysteine-targeting functionality which allows these electrophilic drugs to inhibit the mutant KRAS^G12C protein also facilitates their binding to cysteine-based sensors in KEAP1, resulting in the upregulation of the NRF2-dependent gene expression program.</p> Conclusions <p>The activation of NRF2 by KRAS-G12C inhibitors represents a unique example of anti-cancer drugs which positively regulate the activity of a protein which is normally considered to be an oncogene. In both the malignant cells of the tumour and immune cells within the microenvironment, activation of NRF2 by electrophilic KRAS inhibitors positively contributes to the clinical efficacy of these drugs by promoting anti-cancer immunity. This unprecedented situation, in which the NRF2-dependent oxidative stress response is induced globally within cancer patients, has a number of important clinical implications, particularly in relation to ongoing combination chemotherapy clinical trials, as well as for selecting patient populations which may derive the most benefit from G12Ci anti-cancer drugs.</p>