FBXO9 promotes anti-tumor immunity via degradation of PD-L1 in pancreatic cancer

Immune checkpoint blockade therapy, particularly those targeting programmed death 1/programmed cell death ligand 1 (PD-1/PD-L1), has been extensively employed to treat various human cancers, significantly improving clinical outcomes. Increasing evidence reveals that the therapeutic efficacy of PD-1/PD-L1 inhibitors depends on the abundance of PD-L1 on cancer cells and tumor-associated stromal cells. Here, we demonstrated that F-box protein 9 (FBXO9) is a novel regulator of PD-L1. We found that increased expression of FBXO9 suppresses tumor growth and promotes cytotoxic T cell activation <i>in vivo</i>. Mechanistically, FBXO9 directly binds to PD-L1 protein and enhances its degradation via ubiquitination, thereby impeding PD-L1 maturation and tumor immune evasion. Meanwhile, the expression of FBXO9 is decreased in pancreatic cancer tissues in comparison to normal tissues. Furthermore, FBXO9 expression correlates inversely with PD-L1 levels, with lower FBXO9 expression being associated with worse clinical outcome. These findings identify FBXO9 as a tumor suppressor via its facilitation of PD-L1 degradation, underscoring the potential of targeting FBXO9 in immunotherapeutic approaches for treating cancers, particularly in combination with anti-PD-L1 therapy.