Multiomics Analysis Reveals CTHRC1+ CAFs Drive Immunosuppressive Niches and Predict Immunotherapy Resistance in Gastric Cancer
Cancer‐associated fibroblasts (CAFs) orchestrate immune‐excluded tumor microenvironment (TME), but the CAF heterogeneity remains incompletely understood in gastric cancer (GC). In this study, we integrated multicohort single‐cell RNA sequencing (scRNA‐seq), spatial transcriptomics, and bulk transcriptomic data to construct a comprehensive atlas of the GC TME. Unsupervised clustering identified eight transcriptionally distinct CAF subpopulations, among which CTHRC1+ CAFs were selectively enriched in tumors and showed the strongest association with T cell exclusion. Pseudotemporal trajectory analysis, gene regulatory network inference, and cell–cell communication analysis revealed that basic helix‐loop‐helix family member e41 (BHLHE41) serves as a key transcription factor driving CTHRC1+ CAF differentiation, whereas spatial analyses demonstrated these fibroblasts contribute to fibrotic niches at the tumor–stroma interface through macrophage migration inhibitory factor (MIF)–mediated signaling. Finally, we developed and validated a CTHRC1+ cancer‐associated fibroblast–related risk signature (CRS) that accurately predicts immunotherapy response across independent cohorts. These findings establish CTHRC1+ CAFs as a critical stromal determinant of immune exclusion in GC, suggesting that targeting the CTHRC1+ CAF‐MIF axis or applying CRS‐guided patient stratification may enhance immunotherapy efficacy.