Nuclear PD-L1 regulates YAP-driven transcription via the PGE2-EP4-YAP-importin α3 axis in solid tumors.

Prostaglandin E2 (PGE2) is synthesized by cyclooxygenase 2 (COX-2) in the arachidonic acid pathway. PGE2 promotes cancer initiation and progression while facilitating chronic inflammation and immunosuppression, partly through regulation of programmed death ligand 1 (PD-L1) in tumor cells and tumor-associated macrophages. PGE2 also modulates Hippo signaling, enhancing nuclear Yes-associated protein-1 (YAP1) activity by preventing its phosphorylation-mediated degradation. However, whether PGE2 can similarly recruit PD-L1 into the nucleus has remained unexplored. Here, we show that PGE2 promotes the nuclear recruitment of PD-L1 in colon and breast cancer cells. Using nuclear co-immunoprecipitation and proximity ligation assays, we found that PGE2 upregulates PD-L1 expression and facilitates its nuclear translocation through YAP and importin-α3. Nuclear PD-L1 (nPD-L1) enhances YAP-mediated transcriptional activity through TEAD-promoter engagement. YAP deficiency blocks PD-L1 nuclear localization, and importin-α3 knockdown prevents the nuclear translocation of both YAP and PD-L1. Pharmacological inhibition of the EP4 or COX-2 significantly reduces nPD-L1 levels. Collectively, our findings identify the PGE2-EP4-YAP-importin-α3 axis as a key regulator of PD-L1 nuclear transport and YAP-driven transcriptional programs. Targeting this pathway may suppress nPD-L1- and Hippo-dependent tumor growth, offering a therapeutic strategy for cancers with elevated YAP activity.