人类表皮生长因子受体2（HER2）是一种在某些癌症中过表达的蛋白质，包括乳腺癌和尿路上皮癌。我们发现HER2存在于某部分结肠癌患者中，这提出了使用抗HER2治疗的可能性。RC48是一种新型抗体药物偶联物（ADC），它由细胞毒性单甲基奥利替宁E（MMAE）和通过链接物连接的抗HER2抗体组成，在HER2表达低（IHC2+/FISH-或IHC+）和高的尿路上皮癌患者中显示出可比较的治疗效果。体外研究使用结肠癌细胞株显示，RC48有效阻止HER2阳性细胞的增殖，表明其作为HER2阳性结肠癌治疗的潜力。机制研究表明，RC48不仅诱导细胞周期停滞，还破坏了HER2介导的cGAS-STING信号抑制，可能激活免疫应答抵抗癌细胞。RC48的使用显著减少了HER2阳性结肠癌的生长，并使HER2阳性结肠癌细胞更容易对免疫治疗产生反应。我们研究的结果将有助于确定RC48作为HER2阳性结肠癌治疗选择的可行性。©2023 作者。

Human epidermal growth factor receptor 2 (HER2) is a protein that is overexpressed in some types of cancer, including breast and urothelial cancer. Here we found that HER2 was present in a portion of colon cancer patients, raising the possibility of using anti-HER2 therapy. RC48, a novel antibody-drug conjugate (ADC) comprising cytotoxic monomethyl auristatin E (MMAE) and an anti-HER2 antibody tethered via a linker, showed a comparable therapeutic effect in both HER2 low expressed (IHC2+/FISH- or IHC+) and high expressed urothelial cancer patients. In vitro studies using colon cancer cell lines showed that RC48 effectively impeded the proliferation of HER2-positive cells, indicating its potential as a treatment for HER2-positive colon cancer. Mechanism study showed that RC48 not only induces cell cycle arrest but also disrupts HER2-mediated restain of cGAS-STING signaling, potentially activating an immune response against the cancer cells. The administration of RC48 significantly reduced the growth of HER2-positive colon cancer and made HER2-positive colon cancer cells more susceptible to immunotherapy. The results of our study will contribute to determining the feasibility of RC48 as a therapeutic option for HER2-positive colon cancer.© 2023. The Author(s).