The m¹A-SFRP2-NFAT/TOX axis governs T cell exhaustion in gastric cancer.

IF 4.8 2区医学 Q2 CELL BIOLOGY

Cellular Oncology Pub Date : 2025-08-11 DOI:10.1007/s13402-025-01096-z

Yifan Liu, Gege Liu, Xuanlin Wang, Xueru Zhang, Junlu Wu, Yaran Li, Yao Lu, Ce Shi, Feng Ye, Ruixin Sun

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引用次数: 0

Abstract

Background: While immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, their efficacy in gastric cancer (GC) remains limited, underscoring the need for mechanistic biomarkers of immune evasion.

Methods: We analyzed m¹A RNA modification patterns in the TCGA-STAD cohort, stratifying patients into three subtypes. Functional assays (including CRISPR-based SFRP2 modulation, NFAT/TOX reporter systems, and ex vivo T-cell exhaustion models) were employed to dissect the m1A-SFRP2-NFAT/TOX axis.

Results: High-m¹A tumors exhibited an immunosuppressive microenvironment dominated by exhausted TIM-3⁺PD-1⁺ T cells and poor ICIs responses. Mechanistically, m¹A-modified transcripts stabilized SFRP2, which activated NFAT1/2-TOX signaling to drive T-cell dysfunction-independent of PD-L1 or TMB. SFRP2 overexpression induced irreversible T-cell exhaustion, while its blockade restored antitumor immunity in preclinical models.

Conclusion: Our study unveils m¹A-dependent epitranscriptomic control of SFRP2 as a novel regulator of the NFAT/TOX-mediated immune evasion axis in GC. The m¹A scoring system may refine patient stratification, and targeting SFRP2 represents a promising strategy to overcome ICI resistance.

Clinical trial number: Not applicable.

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m1A-SFRP2-NFAT/TOX轴调控胃癌中的T细胞衰竭。

背景：虽然免疫检查点抑制剂（ICIs）已经彻底改变了癌症治疗，但它们在胃癌（GC）中的疗效仍然有限，这强调了对免疫逃避机制生物标志物的需求。方法：我们分析了TCGA-STAD队列中的m1A RNA修饰模式，将患者分为三个亚型。功能分析（包括基于crispr的SFRP2调节、NFAT/TOX报告系统和离体t细胞衰竭模型）被用于解剖m1A-SFRP2-NFAT/TOX轴。结果：高m1a肿瘤表现出以耗尽的TIM-3+PD-1+ T细胞为主的免疫抑制微环境和较差的ICIs反应。在机制上，m1a修饰的转录物稳定了SFRP2，激活了NFAT1/2-TOX信号，从而驱动t细胞功能失调，而不依赖于PD-L1或TMB。在临床前模型中，SFRP2过表达诱导了不可逆的t细胞衰竭，而其阻断则恢复了抗肿瘤免疫。结论：我们的研究揭示了m1a依赖的SFRP2的表转录组控制是GC中NFAT/ xo介导的免疫逃避轴的新调节剂。m1A评分系统可以细化患者分层，靶向SFRP2是克服ICI耐药的一种有希望的策略。临床试验号：不适用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular Oncology ONCOLOGY-CELL BIOLOGY

CiteScore

10.30

自引率

1.50%

发文量

审稿时长

12 months

期刊介绍： The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.