Background Neurotrophic factors (NFs) are critical for neural development, survival, and function. Emerging evidence suggests their involvement in tumorigenesis, progression, and therapy resistance. However, their comprehensive prognostic and therapeutic implications in colorectal cancer (COAD) remain largely unexplored. Methods We systematically identified neurotrophic factor‐related genes (NFRGs) and constructed a prognostic signature using transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO, dataset GSE39582) cohorts. Differential expression analysis and functional enrichment (Gene Ontology GO and Kyoto Encyclopedia of Genes and Genomes KEGG), univariate, and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analyses were employed to develop a risk model. The model was validated for its ability to stratify patients by overall survival (OS), tumor microenvironment (TME), immune cell infiltration, response to immunotherapy, and chemosensitivity. Single‐cell RNA sequencing (scRNA‐seq) analysis and cell–cell communication inference were performed to validate the findings at a cellular level. Results A robust 12‐gene NFRG signature was established, effectively stratifying COAD patients into high‐ and low‐risk groups with distinct OS. The high‐risk group was characterized by enriched epithelial–mesenchymal transition (EMT) pathways, an immunosuppressive TME with increased cancer‐associated fibroblast (CAF) and M2 macrophage infiltration, and a higher tumor mutation burden. The risk score served as an independent prognostic factor and correlated with advanced clinical stages, BRAF mutation status, and Consensus Molecular Subtypes (CMS). Critically, high‐risk patients exhibited higher TIDE scores, increased CD274 (PD‐L1) expression, and greater potential response to immune checkpoint blockade, alongside reduced sensitivity to 5‐fluorouracil. scRNA‐seq analysis pinpointed epithelial cells as the primary source of NFRG expression, and CellChat analysis revealed enhanced intercellular communication, particularly involving Schwann cell–derived SPP1 signaling, in high‐risk tumors. Conclusion We established and validated a novel NFRG‐based risk model that accurately predicts prognosis, delineates the immune landscape, and informs therapeutic strategies in COAD. This signature presents a promising biomarker for personalized treatment stratification, potentially guiding immunotherapy decisions.
Zuo et al. (Thu,) studied this question.
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