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

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

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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 epithelial-specific Cpt1a-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 blockade-induced anti-tumor immunity and tumoral ferroptosis in tumor-bearing mice.The results illustrate the potential of a mechanism-guided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CSCs to improve the efficacy of lung cancer immunotherapy.

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

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Department of Immunology,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences

School of Basic Medicine,Peking Union Medical College,Beijing 100005,China

Collaborative Innovation Center for Biotherapy,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences

Department of Lung Cancer Surgery,Tianjin Medical University General Hospital,Tianjin 300052,China

Immunology Research Center,National Health Research Institutes,Zhunan,Miaoli,Taiwan,ROC

Department of Immunology,Nankai University,Tianjin 300071,China

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国家自然科学基金国家自然科学基金国家自然科学基金Bilateral Inter-Governmental Science and Technology Cooperation Project from Ministry of Science and Technology of China中央高校基本科研业务费专项

8237310081972795822732202018YFE01143003332022140

2024

10.1038/s41392-024-01772-w

信号转导与靶向治疗(英文)

信号转导与靶向治疗(英文)

CSTPCD
ISSN：
年,卷(期)：2024.9(4)
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