Zhang Ying, Du Jing, Cui Xiaohong, Ling Yuhang, Tang Chengwu
Zhejiang University School of Medicine, Hangzhou, 310058, China.
Central Laboratory, First Affiliated Hospital of Huzhou University, Huzhou, 313000, China.
Cell Death Discov. 2025 Jul 28;11(1):347. doi: 10.1038/s41420-025-02652-0.
Colorectal cancer is a malignant tumor of the colon or rectum, with approximately 150,000 new cases each year. Current treatment strategies, such as surgery, chemotherapy, radiotherapy, and immunotherapy, face challenges ranging from cancer recurrence, drug resistance to significant toxicity. Therefore, these patients urgently need more effective treatments. Ferroptosis, a novel form of cell death characterized by iron-dependent lipid peroxidation, has emerged as a promising new approach for treating colorectal cancer. Inactivation of phospholipid hydroperoxide glutathione peroxidase (GPX4) or the cysteine/glutamate antiporter SLC7A11 leads to the depletion of cellular glutathione (GSH), resulting in lipid peroxidation and subsequent ferroptosis. Here, we found that CDH17 and GUCY2C are co-overexpressed in colorectal cancer cells and developed a bispecific antibody-drug conjugate (BsADC) targeting CDH17 and GUCY2C, conjugated with the ferroptosis inducer RSL3 (a GPX4 inhibitor). Experimental results showed that, compared to monoclonal antibody ADCs, BsADC exhibits better binding and internalization activities, and could inhibit tumor cell proliferation more effectively. Moreover, the BsADC displayed an advantageous safety profile in mice. These findings suggest that the CDH17-GUCY2C BsADC, which induces ferroptosis in tumor cells, could be a promising new treatment for colorectal cancer.
结直肠癌是结肠或直肠的恶性肿瘤，每年约有15万新发病例。当前的治疗策略，如手术、化疗、放疗和免疫疗法，面临着从癌症复发、耐药到严重毒性等诸多挑战。因此，这些患者迫切需要更有效的治疗方法。铁死亡是一种以铁依赖性脂质过氧化为特征的新型细胞死亡形式，已成为治疗结直肠癌的一种有前景的新方法。磷脂氢过氧化物谷胱甘肽过氧化物酶（GPX4）或半胱氨酸/谷氨酸反向转运体SLC7A11的失活会导致细胞内谷胱甘肽（GSH）耗竭，从而导致脂质过氧化及随后的铁死亡。在此，我们发现CDH17和GUCY2C在结直肠癌细胞中共同过表达，并开发了一种靶向CDH17和GUCY2C的双特异性抗体药物偶联物（BsADC），与铁死亡诱导剂RSL3（一种GPX4抑制剂）偶联。实验结果表明，与单克隆抗体ADC相比，BsADC表现出更好的结合和内化活性，并且能更有效地抑制肿瘤细胞增殖。此外，BsADC在小鼠中显示出良好的安全性。这些发现表明，可诱导肿瘤细胞发生铁死亡的CDH17-GUCY2C BsADC可能是一种有前景的结直肠癌新疗法。
