Background Immunotherapy is a promising anti-cancer strategy in hepatocellular carcinoma (HCC). However, a limited number of patients can benefit from it. There are currently no reliable biomarkers available to find the potential beneficiaries. Methylcytosine (m5C) is crucial in HCC, but its role in forecasting clinical responses to immunotherapy has not been fully clarified. Methods In this study, we analyzed 371 HCC patients from The Cancer Genome Atlas (TCGA) database and investigated the expression of 18 m5C regulators. We selected 6 differentially expressed genes (DEGs) to construct a prognostic risk model as well as 2 m5C-related diagnostic models. Results The 1-, 3-, and 5-year area under the curve (AUC) of m5C scores for the overall survival (OS) was 0.781/0.762/0.711, indicating the m5C score system had an ideal distinction of prognostic prediction for HCC. The survival analysis showed that patients with high-risk scores present a worse prognosis than the patients with low-risk scores (p< 0.0001). We got consistent results in 6 public cohorts and validated them in Xiangya real-world cohort by quantitative real-time PCR and immunohistochemical (IHC) assays. The high-m5C score group was predicted to be in an immune evasion state and showed low sensitivity to immunotherapy, but high sensitivity to chemotherapy and potential targeted drugs and agents, such as sepantronium bromide (YM-155), axitinib, vinblastine and docetaxel. Meanwhile, we also constructed two diagnostic models to distinguish HCC tumors from normal liver tissues or liver cirrhosis. Conclusion In conclusion, our study helps to early screen HCC patients and select patients who can benefit from immunotherapy. Step forwardly, for the less likely beneficiaries, this study provides them with new potential targeted drugs and agents for choice to improve their prognosis.

中文翻译：

---

基于 m5C 调节因子的预后分层可作为肝细胞癌免疫治疗的新型生物标志物。

背景 免疫疗法是一种有前途的肝细胞癌 (HCC) 抗癌策略。然而，有限数量的患者可以从中受益。目前没有可靠的生物标志物可用于寻找潜在的受益者。甲基胞嘧啶 (m5C) 在 HCC 中至关重要，但其在预测对免疫治疗的临床反应中的作用尚未完全阐明。方法 在这项研究中，我们分析了来自癌症基因组图谱 (TCGA) 数据库的 371 名 HCC 患者，并研究了 18 个 m5C 调节因子的表达。我们选择了 6 个差异表达基因 (DEG) 来构建预后风险模型以及 2 个 m5C 相关诊断模型。结果 m5C 评分对总生存期 (OS) 的 1 年、3 年和 5 年曲线下面积 (AUC) 分别为 0.781/0.762/0.711，表明 m5C 评分系统对 HCC 的预后预测具有理想的区别。生存分析显示，高风险评分的患者比低风险评分的患者预后更差（p<0.0001）。我们在 6 个公共队列中获得了一致的结果，并通过定量实时 PCR 和免疫组织化学 (IHC) 测定在湘雅真实世界队列中验证了它们。高 m5C 评分组预计处于免疫逃避状态，对免疫治疗的敏感性较低，但对化疗和潜在的靶向药物和制剂（如司潘溴铵 (YM-155)、阿西替尼、长春碱和多西他赛）敏感性较高。同时，我们还构建了两种诊断模型来区分HCC肿瘤与正常肝组织或肝硬化。结论 总之，我们的研究有助于早期筛查 HCC 患者并选择可以从免疫治疗中受益的患者。更进一步，对于不太可能的受益者，这项研究为他们提供了新的潜在靶向药物和药剂供选择，以改善他们的预后。