Intracellular PD-L1: Functions, Regulation, and Therapeutic Implications

Programmed death-ligand 1 (PD-L1) has long been characterized as a membrane-bound immune checkpoint ligand that suppresses antitumor immunity through engagement with PD-1 on T cells. This canonical understanding has underpinned the development of therapeutic antibodies that have revolutionized cancer treatment. However, PD-1/PD-L1 immunotherapy still has limitations such as poor response rates and post-treatment resistance. Notably, emerging evidence reveals that the roles of PD-L1 extend beyond its membrane-bound form, with substantial pools residing in the cytoplasm, nucleus, organelles, and extracellular vesicles. These intracellular PD-L1 populations perform distinct, often immune-independent functions including transcriptional regulation, mRNA stability control, DNA damage response modulation, and metabolic reprogramming. This review examines the subcellular localization of PD-L1, the mechanisms governing its trafficking and compartmentalization, its compartment-specific biological functions, and the corresponding clinical significance. Understanding the full spectrum of PD-L1 biology is essential for developing more effective immunotherapeutic approaches and promoting individualized treatment strategies.