Copper Chelate Targeting Externalized Phosphatidylserine Inhibits PD-L1 Expression and Enhances Cancer Immunotherapy

Inhibitors of the PD-1/PD-L1 immune checkpoint have revolutionized cancer treatment. However, the clinical response remains limited, with only 20% of patients benefiting from treatment and approximately 60% of PD-L1-positive patients exhibiting resistance. One key factor contributing to resistance is the externalization of phosphatidylserine (PS) on the surface of cancer cells, which suppresses immune responses and promotes PD-L1 expression, further hindering the efficacy of PD-L1 blockade therapies. Here, we introduce a copper chelate composed of a terpyridine–Cu complex with a farnesol tail designed to selectively target and cap the externalized PS on cancer cells. This approach not only promotes dendritic cell maturation and effector T-cell proliferation and tumor infiltration but also significantly inhibits PD-L1 expression, thereby amplifying T-cell-mediated immune responses. Our results demonstrate that this strategy induces robust immunological memory and leads to the eradication of tumors in over 70% of mice with colorectal and melanoma cancers. These findings highlight a promising, antibody-independent strategy for cancer immunotherapy where targeting externalized PS could overcome current limitations of checkpoint blockade therapies.