Development and Validation of a Prognostic Model for Lung Adenocarcinoma Based on CAF-Related Genes: Unveiling the Role of COX6A1 in Cancer Progression and CAF Infiltration

Lung adenocarcinoma (LUAD), the predominant subtype of non-small cell lung cancer (NSCLC), presents significant challenges in early diagnosis and personalized treatment. Recent research has focused on the role of the tumor microenvironment, particularly tumor-associated fibroblasts (CAFs), in tumor progression. This study systematically analyzed CAF immune infiltration-related genes to construct a prognostic model for LUAD, confirming its predictive value for patient outcomes. The risk score derived from CAF-related genes (CAFRGs) was negatively correlated with immune microenvironment scores and linked to the expression of immune checkpoint genes, indicating that high-risk patients may exhibit immune escape characteristics. Analysis via the TIDE tool revealed that low-risk patients had more active T-cell immune responses. The risk score also correlated with anti-tumor drug sensitivity, particularly to doramapimod. Notably, <i>COX6A1</i> emerged as a key gene in the model, with its upregulation associated with immune cell infiltration and immune escape. Further in vitro experiments demonstrated that <i>COX6A1</i> regulates LUAD cell migration, proliferation, and senescence, suggesting its role in tumor immune evasion. Additionally, further co-culture studies of lung cancer cells and fibroblasts revealed that <i>COX6A1</i> knockdown promotes the expression of CAF-related cytokines, enhancing CAF infiltration. Overall, this study provides a foundation for personalized treatment of LUAD and highlights <i>COX6A1</i> as a promising therapeutic target within the tumor immune microenvironment, guiding future clinical research.