Mohamady Farouk Abdalsalam Nada, Liang Zihao, Kashaf Tariq Hafiza, Ibrahim Abdulrahman, Li Rong, Wan Xiaochun, Yan Dehong
Guangdong Immune Cell Therapy Engineering and Technology Research Center, Center for Protein and Cell-Based Drugs, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
University of Chinese Academy of Sciences, Beijing 100864, China.
Biology (Basel). 2024 Nov 19;13(11):949. doi: 10.3390/biology13110949.
Although ferroptosis inducers trigger ferroptotic tumor cells and immune cells in the tumor microenvironment (TME), imidazole ketone erastin (IKE)'s induction of ferroptosis shows no effect on tumor growth in immunocompetent tumor-bearing mice due to the presence of myeloid-derived suppressor cells (MDSCs). Treatment of the carnitine palmitoyltransferase 1a (CPT1A)-specific inhibitor decreases the immunosuppressive function of MDSCs and enhances ferroptotic inducer-initiated tumor cell ferroptosis. However, whether blocking CPT1A could enhance IKE-induced MDSC ferroptosis and thereby inhibit tumor growth is still unclear. Here, we report that a CPT1A-specific inhibitor, etomoxir sodium salt (Eto), and IKE combined treatment increased MDSC ferroptosis. Interestingly, the combination treatment of Eto and IKE blocked MDSCs' immunosuppressive function and accumulation by downregulating the expression of SLC7A11, GPX4, and ARG1 while promoting T-cell proliferation and infiltration into tumor tissues to enhance cancer therapy. These data provide a rationale for the combination therapy of a specific CPT1A inhibitor, Eto, with IKE in clinical settings.
尽管铁死亡诱导剂可触发肿瘤微环境（TME）中的铁死亡肿瘤细胞和免疫细胞，但由于髓源性抑制细胞（MDSC）的存在，咪唑酮埃拉斯汀（IKE）诱导的铁死亡对免疫健全的荷瘤小鼠的肿瘤生长没有影响。肉碱棕榈酰转移酶1a（CPT1A）特异性抑制剂的治疗可降低MDSC的免疫抑制功能，并增强铁死亡诱导剂引发的肿瘤细胞铁死亡。然而，阻断CPT1A是否能增强IKE诱导的MDSC铁死亡，从而抑制肿瘤生长仍不清楚。在此，我们报告CPT1A特异性抑制剂依托莫昔钠（Eto）与IKE联合治疗可增加MDSC铁死亡。有趣的是，Eto与IKE的联合治疗通过下调SLC7A11、GPX4和ARG1的表达，阻断了MDSC的免疫抑制功能和积累，同时促进T细胞增殖并浸润到肿瘤组织中，从而增强癌症治疗效果。这些数据为在临床环境中使用特定的CPT1A抑制剂Eto与IKE联合治疗提供了理论依据。
