Ubiquitin-Specific Peptidase 9X Inhibition for Antitumor Immunity Via Programmed Death Ligand 1 Ubiquitination and T-Cell Activation

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor clinical outcomes. Growing understanding of the roles of ubiquitin-specific peptidase 9X (USP9X) in various diseases, particularly cancer, has positioned the protein as a promising target for the development of innovative therapeutic strategies. This study examined the function of USP9X in PDAC development using PDAC cell lines and a xenograft mouse model. Nanoparticle–peptide complexes were used to target pancreatic tumors and achieve USP9X knockdown selectively. USP9X expression was positively correlated with and directly modulated programmed death ligand 1 (PD-L1) levels in cancer cells. USP9X inhibition augmented T-cell antitumor activity by promoting T-cell activation and suppressing PD-L1 expression. These findings indicated that USP9X regulates PD-L1 stability through ubiquitin-mediated degradation, enhances T-cell responses, and activates local immunity against cancer cells. Our novel therapeutic approach, designed to counteract tumor immune evasion, has the potential to inhibit tumor growth effectively.