Collectively, we screened the six LMGs including CYP19A1, FABP4, LRP2, SLCO1A2, PPARGC1A and ALOXE3, and constructed a signature to predict prognosis and immunotherapeutic response in colon cancer, which was extendedly and externally validated. The gene discussed is ALOXE3; the disease is malignant colon neoplasm.