Immunotherapy has revolutionized cancer treatment, yet the efficacy of immunotherapeutic approaches remains limited. Resistance to ferroptosis is one of the reasons for the poor therapeutic outcomes in tumors with Kelch-like ECH-associated protein 1 (KEAP1) mutations. However, the specific mechanisms by which KEAP1-mutant tumors resist immunotherapy are not fully understood. In this study, we showed that the loss of function in KEAP1 results in resistance to ferroptosis. We identified NAD(P)H Quinone Dehydrogenase 1 (NQO1) as a transcriptional target of nuclear factor erythroid 2–related factor 2 (NRF2) and revealed that inducing NQO1-mediated ferroptosis in KEAP1-deficient tumors triggers an antitumor immune cascade. Additionally, it was found that NQO1 protein levels could serve as a candidate biomarker for predicting sensitivity to immunotherapy in clinical tumor patients. We validated these findings in several preclinical tumor models. Overall, KEAP1 mutations define a unique disease phenotype, and targeting its key downstream molecule NQO1 offers new hope for patients with resistance to immunotherapy.

中文翻译：

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靶向 NQO1 诱导免疫治疗耐药 KEAP1 缺陷型癌症的铁死亡并触发抗肿瘤免疫


免疫疗法彻底改变了癌症治疗，但免疫治疗方法的疗效仍然有限。对铁死亡的耐药性是 Kelch 样 ECH 相关蛋白 1 （KEAP1） 突变肿瘤治疗效果不佳的原因之一。然而，KEAP1 突变肿瘤抵抗免疫治疗的具体机制尚不完全清楚。在这项研究中，我们表明 KEAP1 的功能丧失导致对铁死亡的抵抗。我们确定 NAD（P）H 醌脱氢酶 1 （NQO1） 是核因子红细胞 2 相关因子 2 （NRF2） 的转录靶标，并揭示了在 KEAP1 缺陷肿瘤中诱导 NQO1 介导的铁死亡会触发抗肿瘤免疫级联反应。此外，研究发现 NQO1 蛋白水平可以作为预测临床肿瘤患者对免疫治疗敏感性的候选生物标志物。我们在几个临床前肿瘤模型中验证了这些发现。总体而言，KEAP1 突变定义了一种独特的疾病表型，靶向其关键下游分子 NQO1 为免疫治疗耐药的患者提供了新的希望。