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

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.