Nuclear PD-L1: an emerging oncogenic driver and promising therapeutic target in cancer

Programmed cell death-ligand 1 (PD-L1) is best known as a membrane immune checkpoint; however, accumulating evidence indicates that PD-L1 can also localize to the nucleus, where it may exert PD-1-independent, cell-intrinsic functions in cancer. Emerging studies associate nuclear PD-L1 (nPD-L1) with aggressive disease, therapeutic resistance, and poor outcomes across multiple malignancies. In this review, we summarize current evidence regarding the regulatory mechanisms that may govern PD-L1 nuclear translocation, including post-translational modifications, stress-responsive signaling, and importin-dependent trafficking. We further discuss how nPD-L1 has been linked to adaptive programs involving DNA damage repair, metabolic rewiring, transcriptional regulation, and tumor microenvironment remodeling in context-dependent models. Clinically, nPD-L1 has potential relevance as a prognostic biomarker and as a candidate indicator of resistance to immunotherapy, radiotherapy, and chemotherapy, although prospective validation remains limited. We also highlight current challenges in detection and quantification, including the need for standardized multiplex imaging and digital pathology approaches. Finally, we discuss emerging therapeutic strategies aimed at disrupting PD-L1 nuclear trafficking or selectively targeting nuclear PD-L1-associated functions. Collectively, these findings support nPD-L1 as an important and potentially actionable dimension of PD-L1 biology that warrants further mechanistic and translational investigation.