Multi-omics profiling unveils biological and clinical insights into pulmonary sarcomatoid carcinoma

Pulmonary sarcomatoid carcinoma (PSC) is a rare yet highly invasive type of lung cancer that remains poorly characterized. Here, we conduct multi-omics analyses of PSC by integrating whole-exome sequencing, transcriptomic, proteomic, and phosphoproteomic data from 86 PSC patients, alongside single-cell RNA sequencing (scRNA-seq) data from 3 patients receiving neoadjuvant chemoimmunotherapy. We find an elevated ferroptosis suppression signature in PSC tumors and demonstrate their vulnerability to ferroptosis by targeting FTL and SLC3A2. Immune landscape characterization reveals an association between cold tumors, pleomorphic carcinoma, and PTEN mutations. Proteomic profiling identifies three distinct patient subtypes, each exhibiting unique features regarding microenvironment dysregulation, genetic alterations, and potential therapeutic targets. scRNA-seq analysis suggests roles of epithelial-mesenchymal transition in the progression from carcinoma cells to sarcomatoid cells and in immunotherapy resistance in PSC. Altogether, this multi-omics characterization of PSC serves as a rich resource for investigating mechanistic insights and identifying potential therapeutic targets.