Clinicopathological characteristics of patients with inoperable non‐small cell lung cancer harboring circulating <scp>NRF2</scp> pathway mutations

Lung cancer is the leading cause of global cancer-related morbidity and mortality, with tobacco smoking as its strongest risk factor. Nuclear factor erythroid 2-related factor 2 (NRF2) is a redox-regulated transcription factor frequently dysregulated in non-small cell lung cancer (NSCLC), leading to aggressive disease and resistance to therapy. In this study, we analyzed circulating cell-free tumor DNA from a real-world cohort to characterize clinicopathological features and identify risk factors associated with oncogenic NRF2 activation in inoperable NSCLC. Key findings were further validated using retrospective datasets. Our results demonstrate that NRF2 pathway-mutated NSCLC represents a smoking-associated, high-risk molecular subtype frequently accompanied by detrimental SMARCA4 mutations. Importantly, these co-occurring mutations cumulatively worsen clinical outcomes independently of other risk factors. We show that NRF2-mutated tumors generally exhibit lower leukocyte infiltration, while high tumor mutation burden independently correlates with increased cytotoxic T lymphocyte density, regardless of NRF2 status. Furthermore, our data indicate that NRF2 activation can be reliably identified through immunohistochemical detection of protein expression of markers AKR1B10 and AKR1C1, both of which correlate with inferior outcomes. As mutations in NRF2-regulating tumor suppressors KEAP1 and CUL3 are not confined to specific hotspot regions, our findings advocate for a multimodal profiling approach combining somatic mutation assessment with protein or transcriptomic evaluation of NRF2 targets. This comprehensive strategy effectively identifies oncogenic NRF2 hyperactivity, enhancing diagnostic accuracy and clinical decision-making in NSCLC management. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.