Identification of vitamin B6 as a PD-L1 suppressor and an adjuvant for cancer immunotherapy.

Interaction of programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) inhibits T cell activation. Tumor tissues can evade immune surveillance by expressing higher levels of PD-L1. Identification of potential regulators of PD-L1 through natural metabolites may contribute to discovering new drugs for immunotherapy. By using a metabolite library screen, we showed that pyridoxal (PL) significantly suppresses PD-L1 expression. Mechanistically, PL accelerates PD-L1 degradation in a proteasome-dependent manner, and STUB1 serves as an E3 ligase during the process. Functionally, PL enhances T cell killing activity by blocking the PD-1/PD-L1 signaling pathway. Thus, we have identified PL as an inhibitor of PD-L1, which provides a feasible option for combination immunotherapy.