进展期肝细胞癌患者 NK 细胞功能改变与葡萄糖代谢特征

Natural killer (NK) cell immunosuppression represents a critical factor in patients with progressive hepatocellular carcinoma (HCC), yet its underlying characteristics at the single-cell level remain poorly defined.

This study investigates the functional and metabolic alterations in NK cells associated with progressive HCC.

We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood samples from six treatment-na ve HCC patients, categorised into progressive and stable disease groups based on a 3-year follow-up. This was complemented by multicolor flow cytometry of peripheral blood, alongside multicolor fluorescence analyses of paired tumour and adjacent tissues.

Our analyses revealed a significant reduction in NK cell proportion and a marked downregulation of immune-related genes in patients with progressive HCC. scRNA-seq further identified a distinct NK cell characterised by high expression of HAVCR2 (TIM3). Compared to TIM3 - NK cells, TIM3 + NK cells exhibited an exhausted phenotype, evidenced by upregulated CD39 and TIGIT, impaired functional capacity (reduced CD107a and IFN- ) and downregulated key glycolytic enzymes (HK2, ATP5a).

Clinically, high TIM3 expression correlated with shorter progression-free survival and an increased risk of tumour progression. Collectively, our findings delineate a state of NK cell immunosuppression and metabolic impairment in progressive HCC, potentially driven by glycolytic reprogramming and establish TIM3 as a critical marker and potential therapeutic target.