In this study, immune-related genes of S100A9, COLEC12, TREM1, and IFIT1 were identified to be associated with TACE refractoriness and integrated to establish a machine-learning based signature with satisfactory performance, which may have the potential to be the immunotherapeutic targets for TACE refractory HCC patients. This evidence concerns the gene S100A9 and hepatocellular carcinoma.