Dauricine induces programmed cell death protein 1 lysosomal degradation in T cells to enhance cytotoxicity against melanoma.

Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on the surface of activated T cells and suppresses immune responses upon binding to programmed cell death ligand 1 (PD-L1). Blockade of the PD-1/PD-L1 axis has emerged as a groundbreaking immunotherapeutic strategy for the clinical treatment of various cancers, including melanoma. Dauricine is a natural alkaloid with tumor-suppressing properties, although its underlying mechanisms remain incompletely understood. In this study, biochemical and immunofluorescence analyses demonstrated that dauricine effectively reduced PD-1 levels in Jurkat T cells through the endosomal-lysosomal pathway, accompanied by enhanced ubiquitination. Dauricine-induced downregulation of PD-1 led to a marked increase in T-cell-mediated killing of melanoma cells. Furthermore, dauricine inhibited the growth and migration of malignant melanoma cells by inducing apoptosis and cell-cycle arrest at the G1 phase. In vivo studies using melanoma xenograft mouse models confirmed that dauricine enhanced T-cell infiltration into tumor tissues and suppressed melanoma growth. Our investigation revealed novel roles of dauricine in promoting T-cell infiltration into tumors and enhancing cytotoxicity against melanoma cells, thereby providing further evidence to support future clinical evaluation of dauricine as a potential therapeutic agent.