Liver cancer ranks fifth in neoplasm frequency and has the second highest rate of cancer-associated mortality worldwide [
1,
2]. Hepatocellular carcinoma (HCC) accounts for 80% of primary liver cancers and 90% of non-metastatic liver tumours [
3‐
5], with approximately 8,54,000 new cases and 8,10,000 deaths per year globally [
6,
7]. The pathology of HCC is multifactorial and involves many steps [
8]. It has been reported that viral hepatitis infection, aflatoxins, alcohol, altered transcriptional regulation, and genetic susceptibility/polymorphisms are all considered significant factors (individually or synergistically) that contribute to the aetiology of HCC. The poor prognosis of HCC is mainly due to a lack of sensitive detection methods at its early stages and a high frequency of both recurrence and metastasis [
9]. Currently, resection surgery, transplantation, targeted chemotherapy, radiation therapy, interventional therapy, and gene therapy are all effective alternative options for HCC [
10,
11]. Although other advanced treatments have been explored, local and regional therapies are still recommended for early-stage disease because few effective options exist for advanced-stage HCC. Recently, however, immune system-associated therapies have been successfully tested in the clinic.
Tumour immunotherapy has revolutionized cancer treatments and has consistently been the focus of attention because of its promising outcomes for advanced HCC [
12,
13]. Active and passive immunotherapies, immune checkpoint inhibitors (ICIs), and therapies targeting the tumour microenvironment constitute major breakthroughs for cancer treatments [
13,
14]. Accumulating evidence has demonstrated that ICIs [e.g., those targeting programmed cell death ligand 1 (PD-1), T cell immunoglobulin mucin domain-containing-3 (TIM3), and cytotoxic T lymphocyte antigen 4 (CTLA4)] in combination with conventional therapies exhibited enhanced anti-tumour effects and broad applicability for cancer patients [
15‐
17]. Despite these considerable achievements, questions remain as to how to improve the efficacy of immunotherapies, how to broaden their application range, and how to better predict immune responses [
17,
18]. Immune system-based models can provide detailed mechanistic insights and be used to categorize patients into low, medium, and high immune response subgroups.
Bioinformatic analyses allow the identification of potential immune-sensitive therapeutic biomarkers, prognostic models can be constructed based on immune system-related genes [
19,
20]. In this study, we performed a comprehensive analysis of HCC-related immune infiltration and constructed a gene-based immune response model for predicting immunotherapy responses and for identifying potential biomarkers for HCC-targeting therapies.