CTSB-positive tumor-associated macrophages shape prognosis and therapeutic response in lung adenocarcinoma

• The heterogeneity of tumor-associated macrophages in lung adenocarcinoma was comprehensively characterized using integrated single-cell and spatial transcriptomic analyses. • CTSB⁺ tumor-associated macrophages were identified as a key cell population associated with poor prognosis in lung adenocarcinoma. • A CTSB⁺ TAM-related prognostic signature (CTRS) was developed and validated across multiple independent LUAD cohorts. • Functional experiments demonstrated that CTSB⁺ TAMs promote lung adenocarcinoma cell proliferation and migration. Lung adenocarcinoma (LUAD) remains a major clinical challenge in assessment of clinical outcomes and therapeutic response. Although tumor-associated macrophages (TAMs) are known as crucial regulators of tumor progression, their heterogeneity and prognostic relevance in LUAD have not been fully elucidated. The heterogeneity of TAMs was detected by integration analyses of single-cell data and spatial transcriptome data. The CTSB + TAM-related signature (CTRS) was developed by machine learning algorithms across four LUAD datasets. Multi-omics analysis and functional experiments were applied to uncover the potential role and mechanism of CTSB + TAMs in LUAD. Single-cell analysis identified CTSB⁺ TAM as a crucial player in LUAD progression with poor prognosis. The spatial co-localization of CTSB⁺ TAMs and tumor cells was confirmed on LUAD slides. Our proposed CTRS was generated and validated in four independent LUAD cohorts, with high scores indicating unfavorable outcomes Furthermore, high CTRS scores were correlated with immunosuppressive status, and poor responses to immune checkpoint blockade. Functional experiments demonstrated the role of CTSB + TAMs in boosting proliferation and migration in LUAD cells. Our research develops CTRS with reliable performance in evaluating patient clinical outcomes in LUAD, highlighting its potential utility in clinical decision-making.