Expression of Ferroptosis-Related Genes Shapes Tumor Microenvironment and Pharmacological Profile in Gastric Cancer

Background: Ferroptosis is a form of regulated cell death that occurs as a consequence of lethal lipid peroxidation. A wealth of studies has demonstrated that ferroptosis profoundly modulated numerous biological behaviors of tumor. However, its natural functions in gastric cancer (GC) remain to be explored. Methods: Firstly, a total of over 1,000 GC patients from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) database were included in our study. Secondly, 32 ferroptosis-related genes were extracted from the ferrDb website. Then, unsupervised clustering was performed to classify patients into three distinct ferroptosis-related clusters. Subsequently, we systematically and comprehensively explored the biological characteristics of each cluster. Finally, we constructed a scoring system, named ferroptosis score, to quantify each cluster and also investigated the predictive therapeutic value of the ferroptosis score for chemotherapy and immunotherapy. Results: Based on the expressions of 32 ferroptosis-related genes, three distinct ferroptosis-related subtypes with various biological characteristics were determined. Integrated analysis showed that cluster 1 is a microsatellite instability (MSI)-like subtype, cluster 2 is an epithelial-mesenchymal transition (EMT)-like subtype, while cluster 3 tends to be a metabolic-like subtype. Prognostic analysis revealed that patients in cluster 2 had a worse overall survival and relapse-free survival. The distribution of the ferroptosis score was significantly different in clusters and gene clusters. The ferroptosis score could predict the biological characteristics of each cluster, the stromal activity, and progression of tumor. The low ferroptosis score group was characterized by the activation of antigen processing and presentation, DNA damage repair pathways, and metabolic pathways, while the high ferroptosis score group was characterized by stromal activation. In response to anticancer drugs, the ferroptosis score was highly negatively associated with drugs targeting MAPK signaling and PI3K/mTOR signaling, while it was positively correlated with drugs targeting the cell cycle, mitosis, and metabolism. Finally, we also proved that the ferroptosis score could serve as a reliable biomarker to predict response to immunotherapy. Conclusion: This work revealed that tumor cells and their surrounding microenvironment could be shaped by varying the activation degrees of ferroptosis. Establishing ferroptosis-related subtypes would guide in predicting the biological features of individual tumors and selecting appropriate treatment protocols for patients.