Li Zi-Zhan, Liu Yi, Zhou Kan, Cao Lei-Ming, Wang Guang-Rui, Wu Jinmei, Yu Yi-Fu, Xiao Yao, Liu Bing, Wu Qiuji, Song Zhiyong, Bu Lin-Lin
State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
Department of Oral & Maxillofacial - Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
Adv Sci (Weinh). 2025 Sep;12(35):e02154. doi: 10.1002/advs.202502154. Epub 2025 Jun 23.
Lymph node metastasis (LNM) is one of the significant characteristics of poor prognosis in oral squamous cell carcinoma (OSCC), strongly associated with high mortality rates. Immunotherapy has emerged as a crucial treatment modality for OSCC LNM, yet its limited response rate severely restricts its clinical application. Cuproptosis, a newly discovered immunogenic cell death (ICD), is often hindered by lipid metabolic reprogramming in tumor cells, which also contributes significantly to the lack of response to immunotherapy. Herein, a metal-organic framework (MOF) nanodrug loaded with orlistat (ORL) is developed, designated as ORL@Cu-MOF. This nanodrug is designed to respond and release under the high glutathione (GSH) stimulus of the tumor microenvironment (TME), thereby inducing cuproptosis and suppressing fatty acid metabolism in OSCC cells. In vivo, ORL@Cu-MOF effectively triggers cuproptosis and inhibits fatty acid metabolism, exerting antitumor effects in mouse models and remodeling the TME. Furthermore, the combination of ORL@Cu-MOF with programmed death receptor-1 (αPD-1) significantly enhances immunotherapy outcomes, transforming "cold tumors" into "hot tumors". This study is the first to report the synergistic use of cuproptosis induction and fatty acid metabolism suppression in the treatment of metastatic cancer, offering novel insights for the care and management of LNM of OSCC.
淋巴结转移（LNM）是口腔鳞状细胞癌（OSCC）预后不良的重要特征之一，与高死亡率密切相关。免疫疗法已成为治疗OSCC-LNM的关键治疗方式，但其有限的反应率严重限制了其临床应用。铜死亡是一种新发现的免疫原性细胞死亡（ICD），常因肿瘤细胞中的脂质代谢重编程而受阻，这也在很大程度上导致了对免疫疗法缺乏反应。在此，开发了一种负载奥利司他（ORL）的金属有机框架（MOF）纳米药物，命名为ORL@Cu-MOF。这种纳米药物旨在在肿瘤微环境（TME）的高谷胱甘肽（GSH）刺激下响应并释放，从而诱导铜死亡并抑制OSCC细胞中的脂肪酸代谢。在体内，ORL@Cu-MOF有效地触发铜死亡并抑制脂肪酸代谢，在小鼠模型中发挥抗肿瘤作用并重塑TME。此外，ORL@Cu-MOF与程序性死亡受体-1（αPD-1）联合使用可显著提高免疫治疗效果，将“冷肿瘤”转变为“热肿瘤”。本研究首次报道了诱导铜死亡和抑制脂肪酸代谢协同用于转移性癌症治疗，为OSCC-LNM的治疗和管理提供了新的见解。
