胃癌异质性转录元程序相关的微环境空间互作单元及临床意义分析OA

Objective To systematically characterize tumor microenvironmental features and spatial cellular interactomes associated with distinct transcriptional meta-program(MP)in gastric cancer,and explore their clinical implications.Methods We integrated 2 gastric cancer single-cell RNA sequencing(scRNA-seq)datasets to identify malignant cell-derived transcriptional MP.The prognostic value was validated in 3 independent bulk transcriptomic cohorts:The Cancer Genome Atlas(TCGA),GSE15459,and GSE66229.Using scRNA-seq,we dissected MP-specific shifts in microenvironmental cell composition and inferred dominant ligand-receptor interactions.Spatial transcriptomics confirmed the co-localization of implicated cell subsets and signaling pairs.Survival analyses were used to access the associations between key cellular signatures/interaction signatures and patient outcomes.Results Four MP from MP1 to MP4 were identified in malignant cells.High expression of MP2 and MP4 significantly correlated with worse overall survival(P<0.05).In MP2-high tumors,SPP1+macrophages were enriched and predicted to interact with T3 neutrophils via the SPP1-CD44 ligand-receptor pair,with spatial co-localization validated.Both SPP1+macrophage signature(P=0.007)and SPP1-CD44 interaction signature(P=0.008)predicted adverse prognosis.In MP4-high tumors,myofibroblastic cancer-associated fibroblast(myCAF)were expanded and showed interaction with exhausted CD8+T cells through the COL6A family-ITGB1 signaling axis,which was also spatially validated.The myCAF signature(P=0.001)and COL6A family-ITGB1 interaction signature(P<0.001)correlated with poorer survival.Conclusion MP2 and MP4 delineate 2 distinct immunosuppressive spatial niches in gastric cancer:SPP1+macrophage-T3 neutrophil and myCAF-exhausted CD8+T cell.These niches likely drive tumor progression via SPP1-CD44 and COL6A family-ITGB1 axes,respectively,providing potential targets for precision immunotherapy.