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Stromal Stiffness-Regulated IGF2BP2 in Pancreatic Cancer Drives Immune Evasion via Sphingomyelin Metabolism

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资源类型：
Pubmed体系：
作者：
Tang Rong[1,2] * ; Zhang Zifeng[3,4] * ; Liu Xiaomeng[2] * ; Liao Yingna[1,2] * ; Chen Yueyue[2,4] ; Xiao Mingming[3,4] ; Li Yangyi[4] ; Zhou Cong[3] ; Tan Zhen[11] ; Zhang Chaoyi[1] ; Chen Chen[1,2] ; Rong Zeyin[1,2] ; Liu Yuan[6] ; Li Pengcheng[3,5] ; Du Qiong[7] ; He Qing[1,2] ; Lei Yubin[8] ; Wu Zijian[9] ; Lu Siyuan[10] ; Xu Jin[1,2] ; Wang Wei[3,5] ; Shi Si[3,4] ; Yu Xianjun[1,2] ;
机构： [1]Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China [2]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [3]Shanghai Pancreatic Cancer Institute, Shanghai, China [4]Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China. [5]Pancreatic Cancer Institute, Fudan University, Shanghai, China [6]Department of Endoscopy, Fudan University Shanghai Cancer Center, Shanghai, China. [7]Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China. [8]Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China. [9]Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China. [10]Department of Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China. [11]Department of Hepatobiliary Pancreatic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
出处：
DOI： 10.1053/j.gastro.2025.03.019
ISSN：

关键词： Pancreatic Cancer Sphingomyelin Metabolism Tumor Microenvironment

摘要：
Immunotherapy has shown promising results in cancer treatment; however, it remains largely ineffective for pancreatic ductal adenocarcinoma (PDAC). N6-methyladenosine (m6A), known for its crucial role in cancer biology, is not yet fully understood regarding immune evasion. This study aims to elucidate the associations and mechanisms linking m6A modification with immune evasion in PDAC and propose strategies for clinical intervention.A multimodal PDAC cohort of 122 patients was developed, integrating transcriptomic profiling, imaging mass cytometry, and m6A quantification to identify m6A regulators associated with immunosuppressive tumor microenvironment (TME) and clinical outcomes. Findings were validated across 6 independent PDAC cohorts. Assays including MeRIP, RIP, and RNA pull-down confirmed that IGF2BP2 binds to targets, whereas scRNA-seq, flow cytometry, and mIHC profiled the TME. Preclinical interventions were tested in PDAC organoids, patient-derived tissue fragments, and humanized mouse models.Our comprehensive analysis identified the m6A reader protein IGF2BP2 as a critical factor associated with poor prognosis in PDAC, linked to reduced effector cell infiltration and a fibrotic TME. High matrix stiffness in PDAC stabilized IGF2BP2, which subsequently promoted sphingomyelin synthesis via SGMS2 up-regulation. This pathway facilitates PD-L1 localization on membrane lipid rafts, enhancing immune evasion. The elastographic properties of PDAC enabled noninvasive screening of patients with overexpressed IGF2BP2/SGMS2. Disrupting sphingomyelin synthesis improved antitumor immunity and suppressed PDAC growth in humanized mice, highlighting immunotherapeutic opportunities for PDAC.These findings emphasize the critical interplay between extrinsic matrix stiffness and intrinsic IGF2BP2-regulated sphingomyelin synthesis, identifying a promising target for immunotherapeutic strategies in PDAC.Copyright © 2025 AGA Institute. Published by Elsevier Inc. All rights reserved.

基金：
This study was jointly supported by the National Natural Science Foundation of China (823B2071), the National Natural Science Foundation of China (92374102), the Shanghai Municipal Science and Technology Major Project (21JC1401500), and the National Natural Science Foundation of China (U21A20374).
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 胃肠肝病学
最新[2025]版：
大类 | 1 区 医学
小类 | 1 区 胃肠肝病学
第一作者：
第一作者机构： [1]Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China [2]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
共同第一作者：
通讯作者：
通讯机构： [1]Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China [2]Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [3]Shanghai Pancreatic Cancer Institute, Shanghai, China [4]Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China.
推荐引用方式(GB/T 7714)：
Tang Rong,Zhang Zifeng,Liu Xiaomeng,et al.Stromal Stiffness-Regulated IGF2BP2 in Pancreatic Cancer Drives Immune Evasion via Sphingomyelin Metabolism[J].Gastroenterology.2025,doi:10.1053/j.gastro.2025.03.019.
APA：
Tang Rong,Zhang Zifeng,Liu Xiaomeng,Liao Yingna,Chen Yueyue...&Yu Xianjun.(2025).Stromal Stiffness-Regulated IGF2BP2 in Pancreatic Cancer Drives Immune Evasion via Sphingomyelin Metabolism.Gastroenterology,,
MLA：
Tang Rong,et al."Stromal Stiffness-Regulated IGF2BP2 in Pancreatic Cancer Drives Immune Evasion via Sphingomyelin Metabolism".Gastroenterology .(2025)

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