biostudies-literatureUnknown8(1)Lee SYResistance to immune checkpoint blockade (ICB) remains a major challenge in lung adenocarcinoma (LUAD), with stromal mechanisms underlying CD8⁺ T cell exhaustion still poorly understood. By integrating single-cell, bulk, and spatial transcriptomic datasets using EcoTyper, we identified a distinct immunosuppressive ecotype, EC10, enriched for TGF-β signaling and epithelial-mesenchymal transition. EC10 exhibited spatial co-localization of fibroblasts, malignant epithelial cells, and exhausted CD8⁺ T cells, and was consistently associated with immune exclusion, poor progression-free survival, and elevated TIDE scores across four ICB-treated LUAD cohorts. Cell-cell communication analyses revealed a dominant TGFB1-SERPINE1 signaling axis originating from fibroblasts, linking stromal remodeling to T cell dysfunction. In contrast, EC12 represented an inflamed, ICB-responsive state enriched in interferon signaling. These findings define EC10 as a spatially organized, fibroblast-driven immunosuppressive ecosystem predictive of ICB resistance, and highlight the therapeutic potential of targeting the TGF-β axis in LUAD.Communications biology1730https://www.ebi.ac.uk/biostudies/studies/S-EPMC12669596biostudies-literatureFibroblast TGF-β signaling defines spatial tumor ecosystems linked to immune checkpoint blockade resistance.PMC12669596Lee SYLee YfalseFibroblast TGF-β signaling defines spatial tumor ecosystems linked to immune checkpoint blockade resistance.Resistance to immune checkpoint blockade (ICB) remains a major challenge in lung adenocarcinoma (LUAD), with stromal mechanisms underlying CD8⁺ T cell exhaustion still poorly understood. By integrating single-cell, bulk, and spatial transcriptomic datasets using EcoTyper, we identified a distinct immunosuppressive ecotype, EC10, enriched for TGF-β signaling and epithelial-mesenchymal transition. EC10 exhibited spatial co-localization of fibroblasts, malignant epithelial cells, and exhausted CD8⁺ T cells, and was consistently associated with immune exclusion, poor progression-free survival, and elevated TIDE scores across four ICB-treated LUAD cohorts. Cell-cell communication analyses revealed a dominant TGFB1-SERPINE1 signaling axis originating from fibroblasts, linking stromal remodeling to T cell dysfunction. In contrast, EC12 represented an inflamed, ICB-responsive state enriched in interferon signaling. These findings define EC10 as a spatially organized, fibroblast-driven immunosuppressive ecosystem predictive of ICB resistance, and highlight the therapeutic potential of targeting the TGF-β axis in LUAD.2025-01-01T00:00:00Z2025 Dec2026-06-05T21:50:16.583Z2026-05-22T03:15:17.762ZS-EPMC126695964132669710.1038/s42003-025-09087-4