Development and validation of manganese metabolism-related genes prognostic model in colorectal cancer and its immunological characteristics.

Background: Colorectal cancer (CRC) is one of the most common malignant tumors, characterized by high invasiveness and mortality. Manganese serves as a pivotal trace mineral that governs the delicate balance between oncogenic development and host immune surveillance. However, the underlying mechanisms of manganese metabolism in CRC progression remain incompletely understood. This study aimed to investigate the prognostic value of manganese metabolism-related genes and their association with tumor microenvironment characteristics in colorectal cancer. Methods: This study integrated colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) datasets from The Cancer Genome Atlas (TCGA) database to construct a training cohort, while utilizing the GSE12945 and GSE29621 cohorts from the Gene Expression Omnibus (GEO) database as independent validation sets. Prognostic genes for CRC were identified through differential expression analysis, weighted gene co-expression network analysis (WGCNA), univariate/multivariate Cox regression analyses, and the least absolute shrinkage and selection operator (LASSO) regression, followed by the construction of a prognostic risk model. Further, CIBERSORT and single-sample gene set enrichment analysis (ssGSEA) algorithms were employed to assess differences in immune cell infiltration levels across sample groups. Additionally, consensus clustering was used to identify molecular subtypes of CRC, aiming to explore its potential heterogeneous characteristics. Results: This study identified six manganese metabolism-related genes (MMRGs) as prognostic genes for CRC and constructed a robust prognostic risk model. Immune infiltration analysis revealed significantly lower levels of immune cell infiltration in the high-risk group, which also demonstrated reduced responsiveness to anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and anti-programmed death-1 (PD-1) antibody therapies. Furthermore, this study further subdivided CRC into two molecular subtypes with distinct characteristics (Group 1 and Group 2). Specifically, Group 2 patients exhibited longer survival times, with significantly higher levels of CD8+ T cell, fibroblast, and neutrophil infiltration in their tumor microenvironments compared to Group 1. Conclusions: This study explored the complex tumor microenvironment and molecular mechanisms of MMRGs in CRC, providing new insights into the pathological mechanism and treatment strategies of CRC.