DescriptionReactive oxygen species play many important roles in cell growth, metabolism, and survival. Elucidation of the key regulatory mechanisms of cellular redox homeostasis and defense against oxidative stress are fundamentally important for biology and medicine. Superoxide dismutase 1 (SOD1), which rapidly converts superoxide anion to H2O2, is a critical component of the cellular antioxidant defense system. However, its role in cancer is not well understood. In this study, I established a physiologically-relevant, non-small cell lung cancer (NSCLC) mouse model, driven by oncogenic K-RAS and p53 knockout (KP), to determine the function and significance of SOD1 in cancer and examine the underlying mechanisms. This study demonstrates that acute ablation of Sod1 accelerates KP tumor initiation and suppresses KP tumor maintenance in vivo. Curiously, although the dismutase activity of SOD1 was essential for SOD1 to sustain the growth of KP tumor-derived cells in vitro, loss of SOD1 did not significantly enhance global ROS levels. This result suggests a novel function for SOD1 in redox signaling that is critical for the growth of KP tumors. Consistently, nuclear SOD1, rather than cytosolic SOD1, was found to be essential for KP tumor growth, indicating that SOD1 modulates nuclear redox signaling to sustain KP cell growth. The results from the transcriptome and metabolomics analyses provide additional evidence that specifically nuclear SOD1 function supports tumor maintenance. Collectively, these studies elucidate novel functions of SOD1 that are essential for lung carcinogenesis.