在人类癌症中，经常观察到 KEAP1-NRF2 通路中的激活突变，并对其进行积极选择，因为它们赋予癌细胞转录因子 NRF2 的细胞保护功能。这导致侵袭性肿瘤的发展，该肿瘤对化疗化合物的治疗具有抗性。最近的临床进展还表明，NRF2 激活的癌症同样对免疫检查点抑制剂药物具有耐药性。由于这些免疫调节疗法的作用机制与 NRF2 的经典细胞保护功能无关，因此尚不清楚异常的 NRF2 活性如何影响免疫系统的抗癌功能。在此背景下，我们发现在人类癌症中，NRF2激活的细胞受到高度免疫编辑，这使得癌细胞能够逃避免疫监视并发展成恶性肿瘤。这种免疫编辑的形式是减少 MHC-I 复合物的抗原呈递，同时减少 NK 细胞激活配体的表达。总之，这些对 NRF2 激活癌症的免疫原性的修饰抑制了免疫效应细胞的浸润和参与，并有助于形成免疫冷肿瘤微环境，这是 NRF2 激活癌症的一个特征。版权所有 © 2023 作者。由 Elsevier B.V. 出版。保留所有权利。

In human cancer, activating mutations in the KEAP1-NRF2 pathway are frequently observed, and positively selected for, as they confer the cytoprotective functions of the transcription factor NRF2 on the cancer cells. This results in the development of aggressive tumours which are resistant to treatment with chemotherapeutic compounds. Recent clinical developments have also revealed that NRF2-activated cancers are similarly resistant to immune checkpoint inhibitor drugs. As the mechanism of action of these immune modulating therapies is tangential to the classical cytoprotective function of NRF2, it is unclear how aberrant NRF2 activity could impact the anti-cancer functionality of the immune system. In this context, we found that in human cancer, NRF2-activated cells are highly immunoedited, which allows the cancer cells to escape immune surveillance and develop into malignant tumours. This immunoediting takes the form of reduced antigen presentation by the MHC-I complex, coupled with reduced expression of activating ligands for NK cells. Together, these modifications to the immunogenicity of NRF2-activated cancers inhibit immune effector cell infiltration and engagement, and contribute to the formation of the immunologically cold tumour microenvironment which is a characteristic feature of NRF2-activated cancers.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.