Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 25 1 2026 01 01 93 107 Lei He Department of Anorectal, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China Zhengxin Chen Department of Anorectal, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China Chang Zhang Department of Anorectal, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China Panyu Zhu Internal Medicine of Traditional Chinese Medicine (Endocrine Diseases), Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China Shiming Dai Department of General Surgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China 2025 08 17 2025 09 17 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. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4552 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4552/2263