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 Elevated HS modification correlated with poor survival and was linked to T cell exhaustion in patients with HCC. The primate-specific oncofetal protein galectin-14 was identified as an upstream regulator of HS synthesis. Galectin-14 promoted HCC progression and immune evasion by inducing contact-dependent CD8 + 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.