Spatial and functional dissection of cancer-associated fibroblasts-mediated immune modulation in H. pylori-associated gastric cancer

作者：Bonan Chen, Hongzhen Tang, Xiaohong Zheng, Fuda Xie, Peiyao Yu, Yang Lyu, Tiejun Feng, Jialin Wu, Jingya Liu, Yi Xu, Alvin H.K. Cheung, Canbin Fang, Zhangding Wang, Shouyu Wang, Justin Chak Ting Cheung, Yujuan Dong, Ruoxi Tian, Yigan Zhang, Cheng Lu, Chi Chun Wong, Jun Yu, William Ka Kei Wu, Elke Burgermeister, Man Tong, Fengbin Zhang, Wei Kang, Kam Tong Leung, Ka‐Fai To · 发表于：Molecular Cancer · 年份：2025 · DOI：10.1186/s12943-025-02490-9 · 被引用次数：11 · 研究领域：Immune cells in cancer、Cancer Cells and Metastasis、Cancer Research and Treatments

Abstract Background Cancer-associated fibroblasts (CAFs) are key regulators of the tumor microenvironment, yet their spatial organization and immunomodulatory functions in H. pylori -associated gastric cancer (GC) remain incompletely understood. Methods We profiled formalin-fixed paraffin-embedded (FFPE) tumors from 71 GC patients using spatial transcriptomics and integrated single-cell RNA-seq from three independent cohorts (China, USA, and Singapore). CAF-immune cell colocalization was quantified by neighborhood enrichment and aggregation index score. Ligand-receptor inference and trajectory analysis resolved CAF signaling and state transitions. To delineate post-transcriptional control, ARE-motif scanning and expression correlations were combined with laser-assisted crosslinking and immunoprecipitation sequencing (LACE-seq) to nominate ZFP36 targets. Immune contexture and prognostic associations were evaluated using CIBERSORT-ABS and Kaplan-Meier analyses in The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) cohorts. Results We first defined the spatial distributions of the four CAF subtypes reported in prior studies and found that their immune associations varied across histologic and infection-defined GC subtypes. In H. pylori -positive tumors, THBS1⁺ CAFs were spatially enriched near regulatory T cells (Tregs) and were associated with local immunosuppression through WNT5-FZD interactions. In parallel, ZFP36 bound AU-rich elements within the FN1 3′ unt...