肺癌是全世界男性和女性癌症死亡的最常见原因之一。目前使用手术、化疗、放疗和免疫疗法的各种组合来治疗肺癌。然而，由于肿瘤突变负荷（TMB）频率较高，预后仍然相对较差。核因子 E2 相关因子 2 (NFE2L2/NRF2) 通常被认为是抗氧化酶和解毒蛋白表达的主要调节因子，并参与细胞保护。相反，NRF2 甚至可以诱导转移并支持肿瘤进展。 Kelch 样 ECH 相关蛋白 1 (KEAP1) 通过 CUL3 介导的泛素化和连续的蛋白酶体降解，在负调节 NRF2 活性中发挥重要作用。大量研究表明，KEAP1/NFE2L2/CUL3基因的遗传改变导致肺癌中NRF2及其靶基因的表达增加。因此，这些研究为 NRF2 在肺癌中的双重作用提供了充足的证据。在这篇综述中，我们通过关注肺癌的细胞系、小鼠模型和转化研究，讨论了 NRF2 信号传导在治疗抵抗中的作用的机制。最后，我们强调了针对 NRF2 抑制的潜在治疗策略，随后讨论了与肺癌中 NRF2 活性相关的生物标志物。总的来说，我们的文章专门详细讨论了 NRF2 信号通路在治疗（尤其是免疫治疗）耐药中的作用，及其在肺癌治疗中的治疗途径。版权所有 © 2024 SEPAR。由 Elsevier España 出版，S.L.U.版权所有。

Lung cancer is one of the most common causes of cancer death in men and women worldwide. Various combinations of surgery, chemotherapy, radiation therapy and immunotherapy are currently used to treat lung cancer. However, the prognosis remains relatively poor due to the higher frequency of tumor mutational burden (TMB). Nuclear factor E2-related factor 2 (NFE2L2/NRF2) is often considered a primary regulator of the expression of antioxidant enzymes and detoxification proteins and is involved in cytoprotection. On the contrary, NRF2 is even known to induce metastasis and support tumor progression. Kelch-like ECH-associated protein 1 (KEAP1) plays an important role in negatively regulating NRF2 activity via CUL3-mediated ubiquitinylation and successive proteasomal degradation. Extensive research has shown that the genetic alterations of KEAP1/NFE2L2/CUL3 genes lead to increased expression of NRF2 and its target genes in lung cancer. Thus, these studies provide ample evidence for the dual role of NRF2 in lung cancer. In this review, we discussed the mechanistic insights into the role of NRF2 signaling in therapy resistance by focusing on cell lines, mouse models, and translational studies in lung cancer. Finally, we highlighted the potential therapeutic strategies targeting NRF2 inhibition, followed by the discussion of biomarkers related to NRF2 activity in lung cancer. Overall, our article exclusively discusses in detail the NRF2 signaling pathway in resistance to therapy, especially immunotherapy, and its therapeutic avenue in the treatment of lung cancer.Copyright © 2024 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.