Tang Dongyang, Lin Shiqi, Zhou Jingbo, Lei Josh Haipeng, Shao Fangyuan, Sun Heng, Chu Xiangpeng, Li Ling, He Lin, Qiao Yunfeng, Xu Xiaoling, Deng Chu-Xia
Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China; Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau SAR, China.
Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China; Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau SAR, China; Rice Research Institute, Guangdong Academy of Agricultural Sciences, Guangzhou, China.
Cell Rep Med. 2025 Jul 15;6(7):102211. doi: 10.1016/j.xcrm.2025.102211. Epub 2025 Jul 2.
Although three proteasome inhibitors are used for liquid tumor treatment, their effectiveness against solid tumors remains inadequate. To address this issue, we employ a drug combination strategy and discover that ammonium tetrathiomolybdate (TM) and AMD3100 can sensitize solid cancer cell lines to proteasome inhibitors. Mechanistically, we find that TM and AMD3100 reduce proteasome activity by decreasing the protein level of PSMB5. This reduction occurs through the activation of the AMP-activated protein kinase (AMPK) pathway, which inhibits STAT3 phosphorylation. Notably, our in vivo studies reveal that drug combinations retard tumor growth dependent on CD8 T cells. The combination of bortezomib with TM or AMD3100 induces cancer cell antigen presentation and the production of CCL5, which together stimulate the recruitment and generation of cytotoxic CD8 T cells. This study identifies synergistic lethal pairs that enhance the effectiveness of bortezomib-centered therapy for breast cancer treatment in a way relied on intact immune system.
尽管三种蛋白酶体抑制剂用于液体肿瘤治疗，但其对实体瘤的有效性仍然不足。为了解决这个问题，我们采用药物联合策略，发现四硫代钼酸铵（TM）和AMD3100可以使实体癌细胞系对蛋白酶体抑制剂敏感。从机制上讲，我们发现TM和AMD3100通过降低PSMB5的蛋白质水平来降低蛋白酶体活性。这种降低是通过激活AMP激活的蛋白激酶（AMPK）途径发生的，该途径抑制STAT3磷酸化。值得注意的是，我们的体内研究表明，药物组合依赖CD8 T细胞延缓肿瘤生长。硼替佐米与TM或AMD3100的组合诱导癌细胞抗原呈递和CCL5的产生，它们共同刺激细胞毒性CD8 T细胞的募集和生成。本研究确定了协同致死对，以依赖完整免疫系统的方式增强以硼替佐米为中心的乳腺癌治疗的有效性。
