Identification of lncRNAs Indicating Immune Pathway Activity for Predicting Prognosis and Immunotherapy Response in Pan‐Cancer

ABSTRACT Background The critical role of long non‐coding RNAs (lncRNAs) in tumor immunity has garnered increasing attention, and immune pathways are key regulatory factors in tumor immune mechanisms. However, current research on the association between lncRNAs and immune pathways remains limited. Therefore, quantifying this association may provide new insights for predicting prognosis and immunotherapy response. Methods A method was developed to classify candidate immune‐related lncRNAs into complex (CIlncRNAs), moderate (MIlncRNAs), and specific (SIlncRNAs) types based on the breadth of their associations with immune pathway activity. The features of these lncRNA types were then compared from multiple aspects. Results The genomic variations and correlations with DNA methylation of three types of immune‐related lncRNAs were significantly different in multiple cancers. CIlncRNAs were more strongly associated with immune infiltration than MIlncRNAs and SIlncRNAs. Lung adenocarcinoma (LUAD) patients were classified into two subtypes based on CIlncRNAs, with one subtype exhibiting better prognosis and higher immune cell infiltration. High expression of CIlncRNAs in immune cells and their role in CD8 + T cell differentiation in LUAD were validated using single‐cell data. Furthermore, a CIlncRNA signature (CIsig) was established for each cancer, and significant differences in overall survival (OS) were observed across risk stratifications in most cancers. Lastly, CIlncRNA was validated in independent datasets for its ability to predict immunotherapy response and enhance the predictive performance of established biomarkers. Conclusions Overall, our analysis innovatively explores the breadth of associations between lncRNAs and immune pathway activity. We identified CIlncRNAs as potential novel biomarkers for predicting patient prognosis and immunotherapy response, offering valuable insights for clinical practice.