UM-6 remodels the tumor immune microenvironment by blocking PD-L1 N-glycosylation and promoting ERAD-mediated degradation in cervical cancer
Cervical cancer remains a major global health burden. Although PD-1/PD-L1 immune checkpoint blockade has expanded treatment options, durable responses are still limited. One key reason is that tumor cells sustain immunosuppression by maintaining high levels of mature, N-glycosylated PD-L1 on the plasma membrane. This limitation highlights the need for approaches that disrupt PD-L1 maturation and stability rather than merely blocking ligand-receptor binding. UM-6, a melittin-derived fusion peptide, addresses this need by retaining antitumor activity while exhibiting markedly lower hemolysis than native melittin. In tumor models, UM-6 slowed tumor progression, reduced proliferation, and increased apoptosis. In parallel, it reshaped the tumor immune microenvironment by enhancing cytotoxic T-cell activity and mitigating PD-1-associated T-cell exhaustion. Mechanistically, UM-6 impaired PD-L1 N-glycosylation and reduced PD-L1 association with STT3A, which led to endoplasmic-reticulum retention, increased polyubiquitination, and accelerated ERAD/proteasome-mediated degradation, ultimately reducing functional PD-L1 at the cell surface. Together, these results support UM-6 as a peptide-based, mechanistically distinct strategy that targets PD-L1 biogenesis to relieve immunosuppression in cervical cancer.