Dysregulated ferroptosis‐related genes indicate potential clinical benefits for anti–PD‐1/PD‐L1 immunotherapy in lung adenocarcinoma

Abstract Background Ferroptosis is an iron‐dependent programmed cell death mechanism that influences the development of malignancy. Lung adenocarcinoma (LUAD) is the most common type of lung cancer with no known cure. Anti–PD‐1/PD‐L immunotherapy is effective for patients with partial LUAD. Therefore, there is an immediate requirement of novel markers to predict the individualised benefits of immunotherapy. Methods We manually collected the ferroptosis‐related gene (FERG) set and employed the Wilcoxon rank‐sum test to identify the differentially expressed FERGs. Subsequently, we constructed a recursive partitioning and regression tree (RPART) model to predict the benefits of anti–PD‐1/PD‐L1 immunotherapy. Subsequently, the ROC curve and AUC were used to evaluate the model efficiency in an independent dataset. Results In this study, we found that the dysregulated FERGs were closely associated with multiple metabolic processes in LUAD. Furthermore, we identified three ferroptosis‐related tumour subtypes (F1, F3 and F3). The F3 subtype exhibited higher immunoactivity and lower tumour purity, mutation count and aneuploidy and had better survival outcomes compared with the other two subtypes, implying that FERGs played an important role in intertumoral immune heterogeneity. We further explored the role of FERGs in the anti–PD‐1/PD‐L1 immunotherapy. We identified a set of three‐FERGs signature ( CD44 , G6PD and ZEB1 ) that acted as a promising indicator (AUC = 0.697) for the prediction of the benefits of anti–PD‐1/PD‐L1 immunotherapy. Conclusion Ferroptosis, as emerging programmed cell death mechanism, was associated with cancer development. We used ferroptosis‐related genes to predict the immunotherapy benefits that may facilitate the development of individualised anti‐cancer treatment strategies.