Galectin-14, a primate-specific oncofetal protein, impairs anti-tumour immunity in hepatocellular carcinoma by driving elevated heparan sulphate modification

BACKGROUND: The liver naturally exhibits robust glycosylation processes, yet how aberrant glycosylation affects hepatocellular carcinoma (HCC) and its underlying mechanisms remains poorly understood. OBJECTIVE: To investigate the role of heparan sulphate (HS) modification in HCC progression and identify its underlying regulatory mechanism. DESIGN: The association of HS with poor prognosis and immune dysfunction was analysed through HCC clinical data and in vivo models. T cell functions were validated in vivo and in vitro via exogenous HS or HS depletion. Transcriptomic screening of HS-high and HS-low tumour clones was performed to identify upstream regulators of HS. Candidate galectin-14 was functionally confirmed through genetic manipulation in vitro and in transgenic mice. Metabolic and protein-interaction studies showed how galectin-14 drives UDP-glycosyl donor production and HS synthesis. RESULTS: T cell exhaustion, partly mediated by FGFR1 signalling on T cells. It reprogrammed glycometabolism to boost synthesis of UDP-glycosyl donors (UDP-Glc, UDP-GlcNAc, UDP-GlcA) required for HS chains. Mechanistically, galectin-14 directly bound UDP-glucose pyrophosphorylase 2 (UGP2), facilitating its oligomerisation and enzymatic activity, thereby fueling HS production. CONCLUSION: This study defines galectin-14 as a key oncofetal regulator of HCC immunosuppression by rewiring UGP2-mediated glycosyl donor production to promote elevated HS modification and T cell dysfunction, highlighting a potential diagnostic marker and promising therapeutic avenue in HCC.