Xu et al. discovered that EGF/EGFR signaling upregulates PD-L2 glycosylation through STAT3-dependent transcriptional activation of FUT8 in patients with head and neck squamous cell carcinoma (HNSCC) resistant to cetuximab; PD-L2 is thereby prevented from polyubiquitination and lysosomal degradation, increasing its membrane accumulation and PD-1 binding affinity. Here, FUT8 is linked to head and neck squamous cell carcinoma.