Fibroblast TGF-β signaling defines spatial tumor ecosystems linked to immune checkpoint blockade resistance.

ABSTRACT: 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

SUBMITTER: Lee SY 

PROVIDER: S-EPMC12669596 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature