Potential Crosstalk Between ANXA1+ Epithelial Cells and FABP4+ TAM Cells of Ferroptosis‐Related Molecular Clusters Promotes an Immunosuppressive Microenvironment in Non‐Small Cell Lung Cancer

The tumor microenvironment (TME) affects tumor initiation, invasion, metastasis, and therapies. Recently, increasing evidence has demonstrated that ferroptosis plays important regulatory roles in tumourigenesis and progression. It is unclear how ferroptosis affects non-small cell lung cancer (NSCLC) progression by remodeling the TME. In this study, the single-cell RNA sequencing (scRNA-seq) data (85,562 cells, n = 18) were employed to reveal the heterogeneity of ferroptosis activation in NSCLC, and identified six ferroptosis-related molecular clusters. We found that ANXA1+ epithelial and FABP4 + TAM subpopulations were key factors in lung cancer progression and TME remodeling. In addition, the cell-cell communication analysis showed that ANXA1-FPR2/FPR1 receptor-ligand pair contributed to the formation of an immunosuppressive TME. Furthermore, we established a novel signature based on ferroptosis-related molecular clusters, and the risk score model may predict survival and response to immunotherapy. We also found that compared with responder, the expression of ANXA1 and FABP4 is higher in progressor, which indicating a higher expression of ANXA1 and FABP4 was associated with a worse response to immunotherapy. Therefore, we concluded that the molecular clusters associated with ferroptosis served as potential prognostic markers and therapeutic targets for NSCLC patients.