Characterizing Stage‐Specific Cellular Dynamics and Microenvironmental Remodeling in Lung Adenocarcinoma by Single‐Cell RNA Sequencing

Early tumors exhibit normoxic immune activation, while advanced stages show hypoxia‐driven immune exhaustion and suppression. Distinct cell populations—including STAT1‐driven exhausted CD8⁺ T cells, POSTN⁺ fibroblasts, FKBP11⁺ plasma cells, C5 tumor cells, and LGMN⁺ macrophages—cooperate to establish a hypoxia‐enriched, immunosuppressive microenvironment that promotes tumor progression Created with BioRender.com. Abstract Lung adenocarcinoma (LUAD) progression involves dynamic remodeling of the tumor microenvironment (TME). However, the stage‐specific dynamics of immune and stromal cell remodeling throughout LUAD progression remain incompletely understood. Here, the study systematically profiles the cellular composition and transcriptional states across multiple LUAD stages, integrating early‐stage patient specimens with publicly available datasets encompassing advanced‐stage disease. The analysis reveals a marked stage‐dependent shift from a proliferative and immune‐activated microenvironment in early LUAD to a hypoxia‐enriched and immunosuppressive landscape in advanced disease. A distinct hypoxia‐adapted epithelial tumor cell subpopulation (C5), exhibiting transcriptional features of metastasis, invasion, and hypoxia, and poor prognosis, is identified. Advanced LUAD featured immunosuppressive LGMN⁺ macrophages and STAT1‐driven exhausted CD8⁺ T cells. FKBP11⁺ plasma B cells exhibited exhaustion‐linked metabolic changes. POSTN⁺ CAFs emerged as central mediators of extracellular matrix (ECM) remodeling and immune exclusion. Collectively, the findings reveal a model of hypoxia‐driven functional convergence, in which distinct TME components co‐evolve toward phenotypes that collectively promote immune evasion, matrix remodeling, and tumor progression. These findings may provide insights into stage‐specific cellular dynamics and highlight promising therapeutic targets for precision immunotherapy strategies. Early tumors exhibit normoxic immune activation, while advanced stages show hypoxia-driven immune exhaustion and suppression. Distinct cell populations—including STAT1-driven exhausted CD8⁺ T cells, POSTN⁺ fibroblasts, FKBP11⁺ plasma cells, C5 tumor cells, and LGMN⁺ macrophages—cooperate to establish a hypoxia-enriched, immunosuppressive microenvironment that promotes tumor progression Created with BioRender.com. Abstract Lung adenocarcinoma (LUAD) progression involves dynamic remodeling of the tumor microenvironment (TME). However, the stage-specific dynamics of immune and stromal cell remodeling throughout LUAD progression remain incompletely understood. Here, the study systematically profiles the cellular composition and transcriptional states across multiple LUAD stages, integrating early-stage patient specimens with publicly available datasets encompassing advanced-stage disease. The analysis reveals a marked stage-dependent shift from a proliferative and immune-activated microenvironment in early LUAD to a hypoxia-enriched and immunosuppressive landscape in advanced disease. A distinct hypoxia-adapted epithelial tumor cell subpopulation (C5), exhibiting transcriptional features of metastasis, invasion, and hypoxia, and poor prognosis, is identified. Advanced LUAD featured immunosuppressive LGMN⁺ macrophages and STAT1-driven exhausted CD8⁺ T cells. FKBP11⁺ plasma B cells exhibited exhaustion-linked metabolic changes. POSTN⁺ CAFs emerged as central mediators of extracellular matrix (ECM) remodeling and immune exclusion. Collectively, the findings reveal a model of hypoxia-driven functional convergence, in which distinct TME components co-evolve toward phenotypes that collectively promote immune evasion, matrix remodeling, and tumor progression. These findings may provide insights into stage-specific cellular dynamics and highlight promising therapeutic targets for precision immunotherapy strategies. Advanced Science, EarlyView.