Abstract

Programmed cell death protein 1/its ligand 1 (PD-1/PD-L1) blockade has revolutionized cancer immunotherapy, yet its efficacy is limited by incomplete checkpoint inhibition and persistent PD-L1 transcription. In this work, lysine acetyltransferase 8 (KAT8) is identified as a nucleator of liquid–liquid phase separation (LLPS)-mediated condensates that concentrate transcription factors to drive sustained PD-L1 transcription and promote immune resistance. Leveraging this mechanism, a PD-1-functionalized hybrid vesicle–liposome platform (PD-1-HVL–siKAT8) is developed to deliver small interfering RNA (siRNA) targeting KAT8 for LLPS modulation and enhanced cancer immunotherapy. In this platform, the PD-1-presenting vesicles enable tumor accumulation and PD-L1 blockade, while the fused liposomes provide efficient siRNA encapsulation and cytosolic release, leading to potent KAT8 silencing and condensate dissolution. This LLPS modulator platform markedly suppresses PD-L1 expression and reshapes the tumor immune microenvironment, augmenting type I interferon signaling, dendritic cell maturation, cytotoxic T-cell activation, and M1-like macrophage polarization. In subcutaneous and recurrent hepatocellular carcinoma models, PD-1-HVL–siKAT8 significantly inhibits tumor growth, prevents recurrence, and extends survival with negligible toxicity. Collectively, this approach integrates PD-L1 blockade with disruption of LLPS-dependent transcription for durable immunotherapy.