机构：[1]Medical College, Guizhou University, Guiyang 550025, China[2]Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing 210096, China[3]The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China[4]Department of Orthopaedics, Zhongda Hospital, Southeast University, 87 Ding Jia Qiao, Nanjing, 210009, Jiangsu Province, P.R. China[5]Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China[6]Nanjing Women and Children’s Healthcare Hospital, Nanjing 210018 China[7]Medical School of Nanjing University, Nanjing 210046, China[8]Shanxi Academy of Advanced Research and Innovation, Shanxi Provincial Key Laboratory of Protein Structure Determination, Taiyuan 030032, China[9]The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Center for Innovative Traditional Chinese Medicine Target and New Drug Research, International Institutes of Medicine, Zhejiang University, 322000, Yiwu, Zhejiang, China[10]Department of Medical Molecular Biology,[11]Department of Pulmonary Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China浙江省肿瘤医院[12]Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Hangzhou, Zhejiang, China浙江省肿瘤医院[13]Wenzhou Medical University, Wenzhou, China[14]Center for Immunology and Hematology, Department of Biotherapy and Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China四川大学华西医院
N6-methyladenosine (m6A) modifications can impact immune responses by regulating different target genes. Here, we demonstrated that the programmed cell death-1 (PD-1) gene PDCD1 undergoes m6A modification, which subsequently impacts T cell function. METTL14 mediated PDCD1 downregulation in T cells by promoting m6A-dependent destabilization of PDCD1 mRNA, a process mediated by YTHDF1/2/3. Heterozygous METTL14 deficiency impaired the activation of CD8+ T cells and increased tumor growth by elevating PD-1 levels. Clinically, METTL14 was negatively associated with PDCD1 levels across various cancer types and with resistance to PD-1-targeted immunotherapy. Moreover, WD6305, which degrades the METTL3-METTL14 complex, cooperated with anti-PD-1 therapy to suppress tumor growth in mice. Collectively, these findings reveal an immunoregulatory axis involving m6A modification of PDCD1 and highlight potential therapeutic strategies to enhance the efficacy of tumor immunotherapy.
基金：
the National Key Research and Development Program of
China (grant number 2022YFC3401000 to S.Gao.), the National Natural Science
Foundation of China (grant numbers 82430094 and 82025029 to S.Gao.; 82203348 to
YM.Gu.; 82025002; 82394411 to HB.Hu. and 82272701 to K.Ren.) and the Start-up
Research Fund of Southeast University (grant number RF1028623018 to S.Gao.).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2025]版：
大类|1 区医学
小类|1 区肿瘤学
最新[2025]版：
大类|1 区医学
小类|1 区肿瘤学
第一作者：
第一作者机构：[1]Medical College, Guizhou University, Guiyang 550025, China[2]Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Southeast University, Nanjing 210096, China
通讯作者：
通讯机构：[11]Department of Pulmonary Surgery, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China[12]Zhejiang Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology (Lung and Esophagus), Hangzhou, Zhejiang, China[13]Wenzhou Medical University, Wenzhou, China
推荐引用方式(GB/T 7714)：
Huang Chang,Wang Xiaodong,Gu Yinmin,et al.METTL14 Enhances Anti-Tumor Immunity through m6A-dependent loss of PD-1[J].Cancer Research.2025,doi:10.1158/0008-5472.CAN-25-0065.
APA：
Huang Chang,Wang Xiaodong,Gu Yinmin,Ren Ke,Zang Haojing...&Gao Shan.(2025).METTL14 Enhances Anti-Tumor Immunity through m6A-dependent loss of PD-1.Cancer Research,,
MLA：
Huang Chang,et al."METTL14 Enhances Anti-Tumor Immunity through m6A-dependent loss of PD-1".Cancer Research .(2025)
医学