ORL@Cu‐MOF Boost Cuproptosis and Suppress Fatty Acid Metabolism for Cancer Lymph Node Metastasis Synergistic Therapy

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.