Integrative Multiomics Nominate GGCT as a Crucial Regulator of Immunosuppression in Colorectal Cancer

Colorectal cancer (CRC) remains a leading cause of cancer‐related mortality worldwide, with tumor microenvironment (TME) heterogeneity playing a critical role in disease progression and therapeutic response. Immune escape (IE) mechanisms facilitate tumor evasion from host immune surveillance, yet their characterization at the single‐cell level in CRC is incomplete. This study integrated single‐cell RNA sequencing (scRNA‐seq) and bulk transcriptomic data from multiple public cohorts to systematically explore IE‐related signatures in CRC. We identified major and minor cell populations within the TME and performed differential gene expression analysis. Using high‐dimensional weighted gene coexpression network analysis (hdWGCNA), we identified gene modules correlated with IE activity. Subsequent survival analysis across six independent cohorts revealed Gamma‐glutamylcyclotransferase (GGCT) as a novel prognostic biomarker associated with poor survival. Functional enrichment analysis indicated GGCT′s involvement in critical oncogenic pathways. Furthermore, GGCT expression correlated with altered immune infiltration profiles and stromal components, suggesting its role in modulating the immunosuppressive TME. Additionally, GGCT demonstrated potential predictive value for response to immunotherapy across multiple datasets. Our findings highlight GGCT as a key player in CRC immune evasion and a promising therapeutic target.