胰腺癌中基质硬度调节的IGF2BP2通过鞘磷脂代谢驱动免疫逃逸。

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

作者信息

Tang Rong, Zhang Zifeng, Liu Xiaomeng, Liao Yingna, Chen Yueyue, Xiao Mingming, Li Yangyi, Zhou Cong, Tan Zhen, Zhang Chaoyi, Chen Chen, Rong Zeyin, Liu Yuan, Li Pengcheng, Du Qiong, He Qing, Lei Yubin, Wu Zijian, Lu Siyuan, Xu Jin, Wang Wei, Shi Si, Yu Xianjun

机构信息

Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

Shanghai Pancreatic Cancer Institute, Shanghai, China; Shanghai Key Laboratory of Precision Medicine for Pancreatic Cancer, Shanghai, China.

出版信息

Gastroenterology. 2025 Mar 28. doi: 10.1053/j.gastro.2025.03.019.

DOI:10.1053/j.gastro.2025.03.019

PMID:40158738

Abstract

BACKGROUND & AIMS: 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.

METHODS

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 single-cell RNA-sequencing, flow cytometry, and multiplex immunohistochemistry profiled the TME. Preclinical interventions were tested in PDAC organoids, patient-derived tissue fragments, and humanized mouse models.

RESULTS

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.

CONCLUSIONS

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.

摘要

背景与目的

免疫疗法在癌症治疗中已显示出有前景的结果；然而，它对胰腺导管腺癌（PDAC）在很大程度上仍然无效。N6-甲基腺苷（m6A）以其在癌症生物学中的关键作用而闻名，但在免疫逃逸方面尚未完全被理解。本研究旨在阐明m6A修饰与PDAC免疫逃逸之间的关联及机制，并提出临床干预策略。

方法

建立了一个包含122例患者的多模态PDAC队列，整合转录组分析、成像质谱流式细胞术和m6A定量，以鉴定与免疫抑制性肿瘤微环境（TME）及临床结局相关的m6A调节因子。研究结果在6个独立的PDAC队列中得到验证。包括MeRIP、RIP和RNA下拉实验在内的检测证实IGF2BP2与靶点结合，而单细胞RNA测序、流式细胞术和多重免疫组化分析了TME。在PDAC类器官、患者来源的组织片段和人源化小鼠模型中测试了临床前干预措施。

结果

我们的综合分析确定m6A阅读蛋白IGF2BP2是与PDAC预后不良相关的关键因素，与效应细胞浸润减少和纤维化TME有关。PDAC中高基质硬度使IGF2BP2稳定，随后通过上调SGMS2促进鞘磷脂合成。该途径促进PD-L1定位在膜脂筏上，增强免疫逃逸。PDAC的弹性成像特性能够对IGF2BP2/SGMS2过表达的患者进行无创筛查。破坏鞘磷脂合成可改善人源化小鼠的抗肿瘤免疫并抑制PDAC生长，凸显了PDAC的免疫治疗机会。