Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, IL, 60637, USA.
Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, University of Chicago, 5758 South Maryland Avenue, Chicago, IL, 60637, USA.
Adv Sci (Weinh). 2024 Sep;11(35):e2403520. doi: 10.1002/advs.202403520. Epub 2024 Jul 16.
The combination of cuproptosis and immune checkpoint inhibition has shown promise in treating malignant tumors. However, it remains a challenge to deliver copper ions and immune checkpoint inhibitors efficiently and simultaneously to tumors. Herein, a mitochondria-targeted nanoscale coordination polymer particle, Cu/TI, comprising Cu(II), and a triphenylphosphonium conjugate of 5-carboxy-8-hydroxyquinoline (TI), for effective cuproptosis induction and programmed cell death-1 (PD-L1) downregulation is reported. Upon systemic administration, Cu/TI efficiently accumulates in tumor tissues to induce immunogenic cancer cell death and reduce PD-L1 expression. Consequently, Cu/TI promotes the intratumoral infiltration and activation of cytotoxic T lymphocytes to greatly inhibit tumor progression of colorectal carcinoma and triple-negative breast cancer in mouse models without causing obvious side effects.
铜死亡与免疫检查点抑制的联合治疗在恶性肿瘤的治疗中显示出了潜力。然而，高效且同时将铜离子和免疫检查点抑制剂递送到肿瘤部位仍然是一个挑战。在此，报道了一种线粒体靶向纳米级配位聚合物粒子 Cu/TI，它由 Cu(II)和 5-羧基-8-羟基喹啉的三苯基膦缀合物（TI）组成，可有效诱导铜死亡和程序性细胞死亡配体 1（PD-L1）下调。在系统给药后，Cu/TI 能够有效地在肿瘤组织中积累，从而诱导免疫原性细胞死亡并降低 PD-L1 的表达。因此，Cu/TI 促进了肿瘤内细胞毒性 T 淋巴细胞的浸润和激活，从而极大地抑制了结直肠癌和三阴性乳腺癌在小鼠模型中的肿瘤进展，且没有引起明显的副作用。
