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

Lei  He; Zhengxin  Chen; Chang  Zhang; Panyu  Zhu; Shiming  Dai

doi:10.18502/ijaai.v25i1.20442

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

DOI: https://doi.org/10.18502/ijaai.v25i1.20442

Keywords: Colorectal cancer; Immunotherapy resistance; Manganese metabolism; Prognosis

Abstract

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.