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In this study, we integrated multicohort single\u2010cell RNA sequencing (scRNA\u2010seq), 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\u2013cell communication analysis revealed that basic helix\u2010loop\u2010helix 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\u2013stroma interface through macrophage migration inhibitory factor (MIF)\u2013mediated signaling. Finally, we developed and validated a CTHRC1+ cancer\u2010associated fibroblast\u2013related 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\u2010MIF axis or applying CRS\u2010guided patient stratification may enhance immunotherapy efficacy.<\/jats:p>","DOI":"10.1155\/humu\/2370955","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T09:23:11Z","timestamp":1784366591000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multiomics Analysis Reveals CTHRC1+ CAFs Drive Immunosuppressive Niches and Predict Immunotherapy Resistance in Gastric 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