Hepatocellular carcinoma (HCC) has high relapse and low 5-year survival rates. Single-cell profiling in relapsed HCC may aid in the design of effective anticancer therapies, including immunotherapies. We profiled the transcriptomes of ∼17,000 cells from 18 primary or early-relapse HCC cases. Early-relapse tumors have reduced levels of regulatory T cells, increased dendritic cells (DCs), and increased infiltrated CD8⁺ T cells, compared with primary tumors, in two independent cohorts. Remarkably, CD8⁺ T cells in recurrent tumors overexpressed KLRB1 (CD161) and displayed an innate-like low cytotoxic state, with low clonal expansion, unlike the classical exhausted state observed in primary HCC. The enrichment of these cells was associated with a worse prognosis. Differential gene expression and interaction analyses revealed potential immune evasion mechanisms in recurrent tumor cells that dampen DC antigen presentation and recruit innate-like CD8⁺ T cells. Our comprehensive picture of the HCC ecosystem provides deeper insights into immune evasion mechanisms associated with tumor relapse.

肝细胞癌 (HCC) 具有高复发率和低 5 年生存率。复发 HCC 中的单细胞分析可能有助于设计有效的抗癌疗法，包括免疫疗法。我们分析了来自 18 个原发性或早期复发 HCC 病例的约 17,000 个细胞的转录组。在两个独立的队列中，与原发性肿瘤相比，早期复发肿瘤的调节性 T 细胞水平降低，树突状细胞 (DC) 增加，浸润的 CD8 ^{+ T 细胞增加。}值得注意的是，复发性肿瘤中的CD8 ^{+ T 细胞过表达}KLRB1(CD161) 并显示出一种先天性的低细胞毒性状态，具有低克隆扩增，这与在原发性 HCC 中观察到的经典衰竭状态不同。这些细胞的富集与较差的预后有关。差异基因表达和相互作用分析揭示了复发性肿瘤细胞中潜在的免疫逃避机制，可抑制 DC 抗原呈递并招募先天样 CD8 ⁺ T 细胞。我们对 HCC 生态系统的全面了解为与肿瘤复发相关的免疫逃避机制提供了更深入的见解。