2. Academic Validation
  3. Ubenimex synergizes with the PD-L1 blockade in gastric cancer by competitively binding LAP3 with UBE3A

Ubenimex synergizes with the PD-L1 blockade in gastric cancer by competitively binding LAP3 with UBE3A

  • Cell Death Dis. 2026 Feb 26;17(1):241. doi: 10.1038/s41419-026-08509-3.
Caixia Zhao 1 2 3,  Jiaxin Li 1,  Jinxiu Zheng 1,  Ming Chi 1,  Ying Shao 1 4,  Yuxin Che 1 4,  Wenjing Chen 1 4,  Jie Dai 1,  Chunxia Chen 5,  Xiaoning Li 6,  Likun Zan 7,  Yu Shi 1 4,  Yujing Duan 1 4,  Lijun Yang 8 9,  Tao Yang 10 11 12
Affiliations

Affiliations

  • 1 School of Basic Medicine, Institute of Cancer Biology, Shanxi Medical University, Jinzhong, 030600, China.
  • 2 Department of Pathology, Heping Hospital affiliated with Changzhi Medical College, Changzhi, 046000, China.
  • 3 Department of Pathology, Changzhi Medical College, Changzhi, 046000, China.
  • 4 Shanxi Center of Technology Innovation for Biomolecular Imaging & Precision Oncology, Jinzhong, 030600, China.
  • 5 Institute of Medical Technology, Shanxi Medical University, Taiyuan, 030001, China.
  • 6 Department of Biochemistry & Molecular Biology, Shanxi Medical University, Taiyuan, 030001, China.
  • 7 Department of Pathology, The Affiliated Cancer Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
  • 8 Department of Pharmacology, Shanxi University of Medicine, Fenyang, 032200, China. [email protected].
  • 9 Ministry of Education Key laboratory of Cellular Physiology, Shanxi Medical University, Taiyuan, 030001, China. [email protected].
  • 10 Key laboratory of Digestive Disease & Organ Transplantation in Shanxi Province, The First Hospital of Shanxi Medical University, Taiyuan, 030000, Shanxi, China. [email protected].
  • 11 Ministry of Education Key Laboratory of Coal Environmental Pathogenicity and Prevention, School of Public Health, Shanxi Medical University, Taiyuan, 030001, China. [email protected].
  • 12 Collaborative Innovation Center for Molecular Imaging of Precision Medicine, Shanxi Medical University, Taiyuan, 030001, China. [email protected].
PMID: 41748538 DOI: 10.1038/s41419-026-08509-3
Abstract

Immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 blockade, represent a cornerstone of treatment for advanced gastric Cancer (GC). However, their clinical efficacy is hampered by low response rates and the development of both primary and acquired resistance, underscoring the need for innovative combination therapies. In this study, we investigate the potential of Ubenimex, an immunomodulator and inhibitor of leucyl Aminopeptidase 3 (LAP3), in enhancing the therapeutic efficacy of PD-L1 blockade in GC. Using a syngeneic GC mouse model, we demonstrate that Ubenimex significantly augments the efficacy of anti-PD-L1 therapy. We further explore the role of LAP3 in GC progression and find that it is highly expressed in both GC tissues and cells, with elevated LAP3 levels correlating with poor prognosis. Functionally, LAP3 facilitates immune evasion through impaired CD8+ T cell infiltration and cytotoxicity in the GC tumor microenvironment (TME). Notably, our findings reveal that LAP3 enhances PD-L1 expression by binding to UBE3A, an E3 ubiquitin Ligase. Ubenimex disrupts the LAP3-UBE3A interaction, leading to restored UBE3A-mediated ubiquitination and degradation of PD-L1. This mechanism reinvigorates CD8+ T cell infiltration and cytotoxic activity within the TME, thereby overcoming resistance to anti-PD-L1 therapy. In conclusion, our study provides a strong rationale for the synergistic potential of Ubenimex in combination with PD-1/PD-L1 blockade, offering a promising strategy to overcome current limitations of ICIs therapy in GC patients.

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