Hepatocellular carcinoma (HCC) is the most malignant and poor-prognosis subtype of primary liver cancer. The scRNA-seq approach provides unique insight into tumor cell behavior at the single-cell level. Cytokine signaling in the immune system plays an important role in tumorigenesis and has both pro-tumorigenic and anti-tumorigenic functions. A biomarker of cytokine signaling in immune-related genes (CSIRG) is urgently required to assess HCC patient diagnosis and treatment. By analyzing the expression profiles of HCC single cells, TCGA, and ICGC data, we discovered that three important CSIRG (PPIA, SQSTM1, and CCL20) were linked to the overall survival of HCC patients. Cancer status and three hub CSIRG were taken into account while creating a risk nomogram. The nomogram had a high level of predictability and accuracy. Based on the CSIRG risk score, a distinct pattern of somatic tumor mutational burden (TMB) was detected between the two groups. The enrichment of the pyrimidine metabolism pathway, purine metabolism pathway, and lysosome pathway in HCC was linked to the CSIRG high-risk scores. Overall, scRNA-seq and bulk RNA-seq were used to create a strong CSIRG signature for HCC diagnosis.