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

## TL;DR

This study shows that FBXO9 helps fight pancreatic cancer by reducing PD-L1, which allows the immune system to attack tumors more effectively.

## Contribution

FBXO9 is identified as a novel regulator of PD-L1 through direct protein interaction and ubiquitination.

## Key findings

- FBXO9 suppresses tumor growth and activates cytotoxic T cells in vivo.
- FBXO9 binds to PD-L1 and promotes its degradation via ubiquitination.
- Lower FBXO9 expression in pancreatic cancer correlates with higher PD-L1 levels and worse outcomes.

## Abstract

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 in vivo. 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.