Gao Fan, You Wei, Zhang Lei, Shen Ai-Zong, Chen Guang, Zhang Ze, Nie Xuan, Xia Lei, Huang Wei-Qiang, Wang Long-Hai, Hong Chun-Yan, Yin Da-Long, You Ye-Zi
Department of Pharmacy, The First Affiliated Hospital of USTC; Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Key Laboratory of Precision Pharmaceutical Preparation and Clinical Pharmacy, Hefei, Anhui 230026, China.
Department of Polymer Science and Engineering, University of Science and Technology of China, Hefei, Anhui 230026, China.
J Am Chem Soc. 2025 Feb 19;147(7):5796-5807. doi: 10.1021/jacs.4c14394. Epub 2025 Jan 11.
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.
PD-1/PD-L1免疫检查点抑制剂彻底改变了癌症治疗方式。然而，临床反应仍然有限，只有20%的患者从治疗中获益，约60%的PD-L1阳性患者表现出耐药性。导致耐药的一个关键因素是癌细胞表面磷脂酰丝氨酸（PS）的外化，这会抑制免疫反应并促进PD-L1表达，进一步阻碍PD-L1阻断疗法的疗效。在此，我们介绍一种由三联吡啶-铜配合物与法尼醇尾组成的铜螯合物，其设计用于选择性靶向并覆盖癌细胞上外化的PS。这种方法不仅促进树突状细胞成熟、效应T细胞增殖和肿瘤浸润，还能显著抑制PD-L1表达，从而增强T细胞介导的免疫反应。我们的结果表明，该策略可诱导强大的免疫记忆，并使超过70%患有结直肠癌和黑色素瘤的小鼠的肿瘤得到根除。这些发现凸显了一种有前景的、不依赖抗体的癌症免疫治疗策略，即靶向外化的PS可克服当前检查点阻断疗法的局限性。
