SLFN11 suppresses PD-L1 through CDK4-mediated BRD4 phosphorylation and ubiquitination by USP10/TRIM21

Pancreatic ductal adenocarcinoma (PDAC) exhibits a dismal prognosis driven by the interplay between dysregulated cell cycle progression in malignant cells and an immunosuppressive tumor microenvironment (TME). Proliferative PDAC subtypes are characterized by heightened immunosuppressive signatures and diminished cytotoxic CD8+ T cell infiltration. Programmed Death-Ligand 1 (PD-L1) expression exhibits cell cycle-dependent fluctuations, thereby suppressing the tumoricidal activity of effector CD8+ T cells and potentiating immune evasion in malignancies. Here, we identify Schlafen family member 11 (SLFN11) as a critical regulator bridging cell cycle dynamics and immune modulation in PDAC. SLFN11 expression is significantly downregulated in pancreatic cancer cell lines, and its ectopic overexpression markedly downregulates CD274 transcription as well as attenuates tumorigenic potential in vitro and in vivo. Mechanistically, SLFN11 suppresses CDK4-dependent phosphorylation of BRD4 at Ser1126, thereby reducing BRD4 association with USP10 while enhancing its interaction with TRIM21, which promotes BRD4 ubiquitination and proteasomal degradation and subsequently suppresses BRD4-mediated transcriptional activation of CD274 (PD-L1). Rescue experiments confirm that BRD4 overexpression reverses the anti-tumor effects of SLFN11, restoring malignant phenotypes including proliferation, invasion, and metastasis. Clinical immunohistochemical analyses of PDAC patient cohorts reveal that low SLFN11 expression in malignant ductal cells is associated with shorter overall survival. Our findings establish SLFN11 as a novel tumor suppressor that constrains PDAC progression by orchestrating post-translational regulation of BRD4, thereby uncovering a druggable axis linking cell cycle control to immune evasion in pancreatic cancer.