The lethality of esophageal squamous cell carcinoma (ESCC), and other epithelial cancers, is primarily due to its aggressive nature and frequent lymphatic metastasis, both of which impact prognosis. In this review, we explore the underlying molecular mechanisms of ESCC lymphatic metastasis, specifically, the functional role of NRF2 and therapeutic strategies. Current data suggest that NRF2 hyperactivation (NRF2high) may promote lymphatic metastasis of ESCC by affecting the extracellular matrix (ECM), epithelial–mesenchymal transition (EMT), lymphangiogenesis, immune evasion, metabolic programming, and Hippo signaling. We also update the latest developments in NRF2 inhibitors, their mechanisms of action, screening strategies, and approaches for evaluating compound efficacy. Finally, we highlight the utility of animal models for mechanistic studies and therapeutic development. We believe elucidation of the functional role of NRF2 in ESCC lymphatic metastasis and developing proper NRF2 inhibitors will greatly improve the clinical prognosis of ESCC in human patients.
食管鳞状细胞癌及其他上皮源性肿瘤的高致死性主要源于其侵袭性强和易发生淋巴转移的特性，这两者均显著影响患者预后。本文系统综述了食管鳞癌淋巴转移的分子机制，重点探讨核因子E2相关因子2的功能作用及靶向治疗策略。现有研究表明，NRF2过度激活可能通过调控细胞外基质重构、上皮-间质转化、淋巴管新生、免疫逃逸、代谢重编程及Hippo信号通路等多种途径促进食管鳞癌淋巴转移。本文同时更新了NRF2抑制剂的最新研究进展，包括其作用机制、筛选策略及药效评估方法。此外，我们强调了动物模型在机制研究和治疗开发中的重要作用。阐明NRF2在食管鳞癌淋巴转移中的功能机制并开发特异性NRF2抑制剂，将有望显著改善食管鳞癌患者的临床预后。
肿瘤(癌症)患者之家