Development and Validation of a Manganese-metabolism and Immune-integrated Gene Signature for Prognosis and Immune Contexture in Patients with Colorectal Cancer

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality globally. Emerging evidence identifies manganese as an important trigger for the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, but prognostic signatures integrating manganese metabolism and immune pathways remain unexplored in CRC. Through analysis of transcriptomic and clinical data from TCGA-CRC and GSE17538 cohorts, we established and validated an eleven-gene manganese metabolism and immune-related signature that robustly stratified CRC patients into distinct risk groups with significant survival differences. High-risk patients exhibited suppressed immune microenvironments with enriched M2 macrophages and Tregs and activation of oncogenic pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) validation confirmed dysregulation of eight signature genes in clinical CRC samples, indicating the model's potential for prognostic prediction and immunotherapeutic stratification. We established a novel MIRGs signature that accurately predicts CRC clinical outcome. Integration of manganese-based agents with immune checkpoint inhibitors (ICIs) represents a potential therapeutic strategy for immunotherapy-resistant CRC.