Identification of Prognosis Signature Based on cGAS-STING Pathway and Its Immunotherapeutic Significance in Lung Adenocarcinoma.

Abstract

Lung adenocarcinoma (LUAD) is a leading cause of cancer-related deaths worldwide, and there is an urgent need to develop personalized prognostic models for effective treatment strategies. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways has been confirmed to engage in multiple cancer progression, prognosis, and immunotherapy benefits. However, the prognostic significance and immunotherapy response of cGAS-STING pathway-associated genes (CSPAGs) in LUAD remain unclear. Herein, we aimed to establish a CSPAG-based prognostic signature for LUAD patients. A total of 139 CSPAGs derived from the GSEA website were enrolled for subsequent analysis. Univariate Cox regression analysis shows that 22 of 139 CSPAGs were associated with LUAD prognosis. Lasso analysis identified 6 CSPAGs (IFNE, NFKB2, POL3RG, TRAF2, TICAM1 and NLRC3) as the most significant prognostic CSPAGs with the best model efficacy. The CSPAG signature classified LUAD patients into low-risk (LR) and high-risk (HR) groups. Kaplan-Meier analysis demonstrated that patients in the LR group had significantly better overall survival (OS) than those in the HR group (p < 0.05 represents statistical significance), indicating the predictive power of the CSPAG signature in LUAD prognosis. The receiver operating characteristic (ROC) curve analysis showed that the area under the curve (AUC) values for the CSPAG signature were higher than those for other well-established predictive factors, suggesting that the CSPAG signature had a higher predictive efficacy. The CSPAG nomogram incorporating clinical factors such as age, TNM status and the CSPAG risk score accurately predicted the OS of LUAD patients at 1, 3, and 5 years, indicating its potential clinical application in LUAD prognosis. Furthermore, we investigated the expression pattern of the 6 signature CSPAGs in different LUAD subpopulations with distinct clinical features. The CSPAG risk score was increased in the immune-high groups, suggesting a positive correlation between immune infiltration degree and CSPAG risk score. There was a heterogenicity of somatic mutation landscape between the two groups. The LR group had a strong immune cell activity, and most immune checkpoints were significantly expressed in the LR group, implying that this group benefited from immune checkpoint blockade (ICB) therapy. In addition, we verified the high predictive accuracy of the CSPAG signature in the GSE31210 and GSE203360 datasets. Taken together, this study established a CSPAG-based prognostic signature for LUAD patients with high predictive efficacy and clinical relevance. The association between CSPAGs and immune infiltration, and ICB therapy response, highlights the potential of the CSPAG signature as a personalized treatment strategy for LUAD patients.