Predicting immunotherapy prognosis and targeted therapy sensitivity of colon cancer based on a CAF-related molecular signature

The role of cancer-associated fibroblasts (CAFs) in modulating the tumor microenvironment (TME) is gaining attention, yet their impact on prognosis and therapeutic response in colon cancer remains unclear. Here, we identified genes associated with CAF infiltration via weighted gene co-expression network analysis (WGCNA) utilizing data from The Cancer Genome Atlas (TCGA) and GSE39582 cohorts. Univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct CAF molecular signatures (CAFscore). Patients were categorized into high and low CAFscore groups to analyze clinicopathological traits, somatic mutations, immune evasion, and treatment responses. In this study, a total of 244 genes were correlated with CAF infiltration, with 11 linked to overall survival. Notably, FSTL3, CRIP2, and SLC2A3 were selected for the CAFscore. A higher CAFscore was associated with poorer prognoses, increased malignancy, and therapeutic resistance, particularly among patients with high tumor mutation burden and microsatellite instability. Furthermore, elevated FSTL3 expression was associated with reduced CD8⁺ T cell infiltration, indicating a suppressive TME. Mechanistically, CAFs may promote immune evasion via NAMPT ligand-receptor interactions based on single-cell RNA sequencing data. Thus, the CAFscore is crucial for personalizing treatment strategies and identifying patients who require more aggressive management.