文献类型：期刊文献

英文题名：METTL3 Inhibition Restores PD-L1 Expression and CD8⁺ T-cell Cytotoxic Function in Immunotherapy-Treated Gastric Cancer

作者：Fang, Ming[1,2,3];Li, Yaling[1,3,4];Wang, Peng[1,5];Wang, Yanan[1,2];Wang, Xiaoqian[1,2];Wa, Xiaoxia[1,2,3];Zhang, Yu[1,2];He, Zhenyu[1,2];Li, Jiawei[1,2,3];Li, Ling[1,2,3];Su, Yun[1,2,3];Zhou, Huinian[6];He, Jianzheng[1,2,3];Liu, Yongqi[1,2,3]

第一作者：房明

通信作者：He, JZ[1];Liu, YQ[1];He, JZ[2];Liu, YQ[2];He, JZ[3];Liu, YQ[3]

机构：[1]Gansu Univ Chinese Med, Key Lab Dunhuang Med & Transformat Prov & Minister, Lanzhou, Peoples R China;[2]Gansu Univ Chinese Med, Prov Level Key Lab Mol Med Major Dis & Prevent & T, Lanzhou, Peoples R China;[3]Gansu Univ Chinese Med, Coll Basic Med, Lanzhou 730000, Peoples R China;[4]Gansu Prov Hosp, NHC Key Lab Diag & Therapy Gastrointestinal Tumor, Lanzhou, Peoples R China;[5]Gansu Univ Chinese Med, Sch Tradit Chinese & Western Med, Lanzhou, Peoples R China;[6]Lanzhou Univ, Hosp 2, Gen Surg Dept, Lanzhou, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Univ Chinese Med, Key Lab Dunhuang Med & Transformat Prov & Minister, Lanzhou, Peoples R China;[2]corresponding author), Gansu Univ Chinese Med, Prov Level Key Lab Mol Med Major Dis & Prevent & T, Lanzhou, Peoples R China;[3]corresponding author), Gansu Univ Chinese Med, Coll Basic Med, Lanzhou 730000, Peoples R China.|[107351d2d02a88e1f325f]甘肃中医药大学基础医学院（敦煌医学研究所）;[10735]甘肃中医药大学;

年份：2025

卷号：13

期号：7

起止页码：1037

外文期刊名：CANCER IMMUNOLOGY RESEARCH

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001522174600005)】；

基金：This work was supported by the National Natural Science Foundation of China (No. 82360864), the Youth Science and Technology Fund Program of Gansu Province (No. 22JR5RA596), the Natural Science Foundation of Gansu Province (No. 22JR11RA116), the Gansu Province Education and Technology Innovation Project (2022QB-097), and the Gansu Province "Double First-Class" Scientific Research Key Project (GSSYLXM-05). We would like to thank DuoMaKe Technology (Beijing) Co., Ltd., for their technical support.

语种：英文

摘要：The efficacy of immunotherapy targeting PD-1/PD-L1 in gastric cancer depends on PD-L1 expression levels and the infiltration of immune cells within the tumor microenvironment (TME). Although methyltransferase-like 3 (METTL3) plays a role in the development and progression of gastric cancer, its mechanism of regulating the TME in gastric cancer remains unclear. In this study, we demonstrated that the expression of PD-L1 is regulated by METTL3. We found that METTL3 mediated N6-methyladenosine (m6A) modification of PDL1 mRNA in the 3 ' untranslated region and induced mRNA degradation through an m6A/YTHDF2-dependent pathway in human gastric cancer cells. METTL3 knockdown or inhibition in gastric cancer cells significantly enhanced Jurkat cell migration and cytotoxic activity. In clinical gastric cancer tissue, a negative correlation was observed between the expression levels of PD-L1 and those of METTL3 or YTHDF2. In vivo, combination treatment with the METTL3 inhibitor STM2457 and PD-1 mAb resulted in a significant reduction in tumor growth, enhanced PD-L1 expression, and increased infiltration of CD8+ T cells. Finally, lower METTL3 expression in tumors correlated with improved sensitivity to anti-PD-1 immunotherapy in patients. Our findings revealed that METTL3-mediated m6A modification of PDL1 mRNA levels represents an epigenetic mechanism regulating antitumor immunity in gastric cancer, and inhibiting METTL3 during PD-1 mAb treatment reshaped the TME, thereby establishing a promising treatment approach for enhancing immunotherapy efficacy in patients with gastric cancer.