2. Academic Validation
  3. UM-6 remodels the tumor immune microenvironment by blocking PD-L1 N-glycosylation and promoting ERAD-mediated degradation in cervical cancer

UM-6 remodels the tumor immune microenvironment by blocking PD-L1 N-glycosylation and promoting ERAD-mediated degradation in cervical cancer

  • Bioorg Chem. 2026 Jul 5:175:109788. doi: 10.1016/j.bioorg.2026.109788.
Dongying Wang 1,  Jiaxing He 2,  Shuying Wu 3,  Shanshan Liu 4,  Hongxin Wang 4,  Tianmin Xu 5
Affiliations

Affiliations

  • 1 Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 4026 Ya Tai Street, Changchun, Jilin 130041, China. Electronic address: [email protected].
  • 2 Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 4026 Ya Tai Street, Changchun, Jilin 130041, China. Electronic address: [email protected].
  • 3 Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 4026 Ya Tai Street, Changchun, Jilin 130041, China. Electronic address: [email protected].
  • 4 Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 4026 Ya Tai Street, Changchun, Jilin 130041, China.
  • 5 Obstetrics and Gynecology Department, The Second Hospital of Jilin University, 4026 Ya Tai Street, Changchun, Jilin 130041, China. Electronic address: [email protected].
PMID: 41916036 DOI: 10.1016/j.bioorg.2026.109788
Abstract

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.

Keywords

CD8(+) T cells; Cervical cancer; ERAD pathway; Immune checkpoint; PD-L1 glycosylation; Tumor microenvironment; UM-6.

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