Targeting the TIGIT/CD155-induced metabolic checkpoint in NK cells restores anti-tumor immunity and suppresses hepatocellular carcinoma growth

Background The TIGIT/CD155 axis is a key immune checkpoint in hepatocellular carcinoma (HCC), but its role in regulating natural killer (NK) cell metabolism and function remains unclear. This study investigates how this axis impairs NK cell anti-tumor immunity via metabolic reprogramming. Methods An HCC mouse model was used for single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) to identify dysregulated pathways in TIGIT high NK cells. A co-culture system consisting of CD155-overexpressing tumor cells and NK cells was established. Molecular interactions were examined by co-immunoprecipitation, western blotting, and immunofluorescence. NK-cell glycolytic activity was assessed by extracellular acidification rate, glucose uptake, and lactate production, and NK-cell function was evaluated by cytokine secretion and cytotoxicity assays. The involvement of the SHP-2/STAT3/GLUT1 axis was further examined using genetic and pharmacological interventions in vitro and in a xenograft model. Results CD155 expression was increased in HCC tissues. TIGIT high NK cells showed transcriptional features consistent with impaired glycolytic activity and functional suppression. CD155 engagement was associated with increased SHP-2 recruitment, reduced STAT3 phosphorylation, and lower GLUT1 expression, accompanied by decreased glycolytic activity. TIGIT blockade restored GLUT1 expression, glycolytic flux, and NK-cell effector function, including IFN-γ production, granzyme B expression, and cytotoxic activity. These effects were weakened by STAT3 inhibition or GLUT1 knockdown. In vivo , TIGIT blockade reduced tumor growth and was associated with increased metabolic and functional markers in NK cells, whereas STAT3 inhibition partially attenuated these effects. Conclusion The TIGIT/CD155 axis is associated with NK-cell dysfunction in HCC through SHP-2-dependent suppression of STAT3/GLUT1-related glycolytic metabolism. These findings suggest that metabolic restoration may represent a potential strategy to improve NK-cell-mediated antitumor immunity in HCC.