Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy

Immunotherapies targeting programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have shown impressive clinical outcomes for multiple tumours. However, only a subset of patients achieves durable responses, suggesting incompletely understood mechanisms of the immune checkpoint pathways. Here, we report that PD-L1 translocates from the plasma membrane into the nucleus through interaction with components of endocytosis and nucleocytoplasmic transport pathways, which is regulated by p300-mediated acetylation and HDAC2-dependent deacetylation of PD-L1. Moreover, PD-L1 deficiency leads to compromised expression of multiple immune response-related genes. Genetically or pharmacologically modulating PD-L1 acetylation blocks its nuclear translocation, reprograms the expression of immune response-related genes and consequently enhances the anti-tumour response to PD-1 blockade. Thus, our results reveal an acetylation-dependent regulation of PD-L1 nuclear localization that governs immune response gene expression, thereby advocating for targeting PD-L1 translocation to enhance the efficacy of PD-1/PD-L1 blockade.