A nine-gene nicotine-metabolism signature predicts prognosis and characterizes the immune landscape in colon adenocarcinoma

Background: Smoking is a preventable cause of colorectal cancer (CRC), and nicotine metabolism may promote tumorigenesis. We aimed to investigate the prognostic significance of nicotine metabolism‑related genes (NRGs) in colon adenocarcinoma (COAD) and to develop a gene signature for patient stratification. Methods: Using the Cancer Genome Atlas COAD cohort, we performed differential expression analysis and weighted gene co-expression network analysis to identify NRGs. Functional enrichment, Cox regression, and least absolute shrinkage and selection operator (LASSO) modelling were applied to build a multigene signature, which was validated in external cohorts. Single-cell transcriptomic data and immune infiltration analyses were used to evaluate gene expression patterns and tumor microenvironmental features. Results: ) was derived; this risk model independently predicted overall survival and showed robust performance across multiple datasets. Single‑cell analyses confirmed cell‑type‑specific expression of these genes. High‑risk scores were associated with altered immune cell infiltration, distinct mutation profiles, and differential drug sensitivity patterns. Conclusions: We propose a novel NRG-based prognostic signature that accurately predicts outcomes in COAD. The model highlights the interplay between nicotine metabolism, ECM remodeling, and immune responses, highlighting genes and pathways that may inform future therapeutic stratification.