Tumor cells can escape from immune killing by binding their programmed death ligand-1 (PD-L1) to the programmed cell death protein 1 (PD-1) of T cells. These immune checkpoint proteins (PD-L1/PD-1) have become very important drug targets, since blocking PD-L1 or PD-1 can recover the killing capability of T cells against tumor cells. Instead of targeting the binding interface between PD-L1 and PD-1, we explored the possibility of regulating the membrane orientation thermodynamics of PD-L1 with ligand-modified ultra-small hydrophobic nanoparticles (NPs) using μs-scale coarse-grained molecular dynamics (MD) simulations in this work. Our MD results indicate that embedded hydrophobic NPs can significantly change the membrane orientation thermodynamics of the extracellular domain of PD-L1, enhancing the probability in the "stand up" state for better binding to PD-1. Meanwhile, embedded hydrophobic NPs promote the tilt of the transmembrane domain of PD-L1. Besides, effects on both extracellular and transmembrane domains are determined by the ligand length and NP concentration. Our study may provide an alternative strategy to achieve PD-L1-related immunotherapy with nanomedicine.