Thus, we established a CAFs-related gene signature including twenty genes (ADAM8, CADM3, CASS4, CDC25C, CYTH3, EPHA6, IGFBP3, LAMP5, LSAMP, MAN1C1, NAV3, NLGN1, NOVA1, RCAN2, S1PR3, SIGLEC1, SLAMF1, SUSD5, TUB, and ZNF385A) through WGCNA, univariate, LASSO, and multivariate Cox regression analysis for predicting the prognosis and therapy response of CRC patients. The gene discussed is S1PR3; the disease is colorectal carcinoma.