Targeting carnitine palmitoyl transferase 1A(CPT1A)induces ferroptosis and synergizes with immunotherapy in lung cancer  

作　　者：Lei Ma Chong Chen Chunxing Zhao Tong Li Lingyu Ma Jiayu Jiang Zhaojun Duan Qin Si Tsung-Hsien Chuang Rong Xiang Yunping Luo 

机构地区：[1]Department of Immunology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,School of Basic Medicine,Peking Union Medical College,Beijing 100005,China [2]Collaborative Innovation Center for Biotherapy,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,School of Basic Medicine,Peking Union Medical College,Beijing 100005,China [3]Department of Lung Cancer Surgery,Tianjin Medical University General Hospital,Tianjin 300052,China [4]Immunology Research Center,National Health Research Institutes,Zhunan,Miaoli,Taiwan,ROC [5]Department of Immunology,Nankai University,Tianjin 300071,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第4期1675-1689,共15页信号转导与靶向治疗（英文）

基　　金：supported by grants from the National Natural Science Foundation of China (NSFC):grant no.82373100 (to C.C.),81972795 (to C.C.)and 82273220 (to Y.L.);the Bilateral Inter-Governmental S&T Cooperation Project from Ministry of Science and Technology of China:grant no.2018YFE0114300 (to R.X.and Y.L);the Fundamental Research Funds for the Central Universities:grant no.3332022140 (to L.M.).

摘　　要：Despite the successful application of immune checkpoint therapy,no response or recurrence is typical in lung cancer.Cancer stem cells(CSCs)have been identified as a crucial player in immunotherapy-related resistance.Ferroptosis,a form of cell death driven by iron-dependent lipid peroxidation,is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with immunotherapy.Metabolic adaption of CsCs drives tumor resistance,yet the mechanisms of their ferroptosis defense in tumor immune evasion remain elusive.Here,through metabolomics,transcriptomics,a lung epithelialspecific Cptla-knockout mouse model,and clinical analysis,we demonstrate that CPT1A,a key rate-limiting enzyme of fatty acid oxidation,acts with L-carnitine,derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8^(+)T cells inactivation in lung cancer.Mechanistically,CPT1A restrains ubiquitination and degradation of c-Myc,while c-Myc transcriptionally activates CPT1A expression.The CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating,thereby suppressing ferroptosis in CSCs.Significantly,targeting CPT1A enhances immune checkpoint blockadeinduced anti-tumor immunity and tumoral ferroptosis in tumor-bearing mice.The results illustrate the potential of a mechanismguided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CsCs to improve the efficacy of lung cancer immunotherapy.

关 键 词：IMMUNOTHERAPY METABOLISM PEROXIDATION 

分 类 号：R730.51[医药卫生—肿瘤]