Abstract
Lung adenocarcinoma (LUAD) remains one of the most lethal malignancies worldwide, with a high mortality rate and unfavorable prognosis. Endoplasmic reticulum (ER) stress is a key regulator of tumour growth, metastasis, and the response to chemotherapy, targeted therapies and immune response. It acts via responding to misfolded proteins and triggering abnormal activation of ER stress sensors and downstream signalling pathways. Notably, the expression patterns of ER-stress-related-genes (ERSRGs) are indicative of survival outcomes, especially in the context of immune infiltration. Through consensus clustering of prognosis-associated ERSRGs, we delineated two distinct LUAD subtypes: Cluster 1 and Cluster 2. Comprehensive analyses revealed significant disparities between these subtypes in terms of prognosis, immune cell infiltration, and tumor progression. Leveraging the robustness of LASSO regression and Multivariate stepwise regression, we constructed and validated an ER Stress-associated risk signature for LUAD. This signature underwent assessments for its prognostic value, correlation with clinical attributes, and interaction within the tumour immune microenvironment. By integrating this signature with multivariate cox analysis of distinct pathological stages, we devised an enhanced nomogram, validated through various statistical metrics, with an area under the curve for overall survival at 1, 3, and 5 years post-diagnosis being 0.79, 0.80, and 0.81, respectively. In conclusion, our findings introduce a composite signature of 11 pivotal ERSRGs, holding promise as a potent prognostic tool for LUAD, and offering insights for immunotherapeutic and targeted intervention strategies.