Usnic acid suppresses cervical cancer cell proliferation by inhibiting PD‐L1 expression and enhancing T‐lymphocyte tumor‐killing activity

Abstract

The programmed cell death 1 (PD‐1)/programmed death ligand 1 (PD‐L1) pathway is abnormally expressed in cervical cancer cells. Moreover, PD‐1/PD‐L1 blockade reduces the apoptosis and exhaustion of T cells and inhibits the development of malignant tumors. Usnic acid is a dibenzofuran compound originating from Usnea diffracta Vain and has anti‐inflammatory, antifungal, and anticancer activities. However, the molecular mechanism of its antitumor effects has not been fully elucidated. In this work, we first observed that usnic acid decreased the expression of PD‐L1 in HeLa cells and enhanced the cytotoxicity of co‐cultured T cells toward tumor cells. Usnic acid inhibited PD‐L1 protein synthesis by reducing STAT3 and RAS pathways cooperatively. It was subsequently shown that usnic acid induced MiT/TFE nuclear translocation through the suppression of mTOR signaling pathways, and promoted the biogenesis of lysosomes and the translocation of PD‐L1 to the lysosomes for proteolysis. Furthermore, usnic acid inhibited cell proliferation, angiogenesis, migration, and invasion, respectively, by downregulating PD‐L1, thereby inhibiting tumor growth. Taken together, our results show that usnic acid is an effective inhibitor of PD‐L1 and our study provide novel insights into the mechanism of its anticancer targeted therapy.