Fibroblast 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. This research identifies a fibroblast-driven immunosuppressive ecosystem in lung adenocarcinoma, linking TGF-β signaling to immune resistance.