Objectives <p>Cytotoxic T lymphocytes (CTLs) are major actors in innate and adaptive antitumor response. We attempted to apply cancer cell-intrinsic CTL evasion genes (CCGs) to identify and verify a risk stratification signature in hepatocellular carcinoma (HCC) patients to assess the prognosis and benefits of immunotherapy, sorafenib treatment and transcatheter arterial chemoembolization (TACE) treatment.</p> Methods <p>We developed a novel prognostic signature including six CCGs was developed by LASSO Cox regression. CIBERSORT, quanTIseq, and ssGSEA algorithms were used to investigated the correlation between the CCG signature and immune cell infiltration. We also assessed the performance of the CCG signature predicting immunotherapy, sorafenib treatment and TACE treatment with independent clinical mRNA sequencing data.</p> Results <p>The area under the curve (AUC) of the CCG signature for predicting 1-, 3-, and 5-year OS was 0.77, 0.70 and 0.70 in the learning cohort, respectively. In the external verification cohort, the AUCs of the CCG signature were 0.71, 0.74 and 0.75. The CCG signature was significantly positively related to both TMB and MSI. In addition, responders had a significantly higher risk score than nonresponders when the signature was applied in urothelial cancer patients with immunotherapy, and the AUC of the CCG signature for predicting the response was 0.65. We further found that responders had a significantly lower risk score than nonresponders in the sorafenib and TACE treatment cohorts, and the AUCs of the CCG signature for predicting the response were 0.87 and 0.76, respectively. Finally, we identified four small molecule compounds negatively related to differentially expressed genes (DEGs) between the two categories of HCC patients, including monensin, etiocholanolone, naringenin, and Prestwick-1103.</p> Conclusions <p>The CCG signature has some clinical significance that may enhance HCC patient outcomes and even help develop novel strategies for HCC patient management.</p>