Programmed death‐ligand 1 nuclear translocation: A novel perspective from membrane localization to nuclear function

The mechanism by which membrane-expressed programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, mediates tumor immune evasion is well established. Recent studies, however, have revealed that PD-L1 can undergo nuclear translocation (nuclear PD-L1, nPD-L1) and contribute to tumor progression through nonimmune-dependent mechanisms. Nuclear translocation of PD-L1 involves p300-mediated acetylation, Huntingtin-interacting protein 1-related protein-dependent endocytosis, and Vimentin-importin α/β pathway-mediated nuclear transport, and is dynamically regulated by histone deacetylase 2-mediated deacetylation. Once localized in the nucleus, PD-L1 promotes angiogenesis and immune evasion by regulating target genes such as early growth response 1. It also participates in nonimmune functions, including DNA damage repair, sister chromatid cohesion, and pyroptosis, exhibiting both pro-tumorigenic and potential tumor-suppressive roles. Moreover, regulation of PD-L1 subcellular localization via MIB2-mediated ubiquitination and small-molecule inhibitors such as BMS1166 offers new insights for targeted therapy. This review systematically summarizes the molecular mechanisms underlying PD-L1 nuclear translocation, its biological functions, roles within the tumor microenvironment, and potential as a biomarker and therapeutic target. Emphasis is placed on addressing functional heterogeneity and mitigating experimental artifacts, which is critical for translational research.