γ-分泌酶作为一种多底物跨膜蛋白酶，广泛存在于多种细胞中。它通过底物裂解控制多种重要的细胞活动。 γ-分泌酶抑制剂（GSI）通过阻断Notch裂解而在癌症抑制中发挥作用，被认为是潜在的癌症治疗策略。目前，GSI 在临床前模型中具有令人鼓舞的表现，但这种成功在临床试验中并没有很好地转化。近年来，许多突破性的发现向我们展示了靶向γ-分泌酶治疗癌症的前景。在此，我们整合近30年来γ-分泌酶及其抑制剂与癌症的大量数据，梳理和讨论γ-分泌酶与癌症的密切联系，以及目前GSI在癌症治疗中的潜力和问题。我们分析了当前 GSI 在临床试验中表现失败的可能原因，并对未来的研究领域提出建议。© 作者。

As a multi-substrate transmembrane protease, γ-secretase exists widely in various cells. It controls multiple important cellular activities through substrate cleavage. γ-secretase inhibitors (GSIs) play a role in cancer inhibition by blocking Notch cleavage, and are considered as potential therapeutic strategies for cancer. Currently, GSIs have encouraging performance in preclinical models, yet this success does not translate well in clinical trials. In recent years, a number of breakthrough discoveries have shown us the promise of targeting γ-secretase for the treatment of cancer. Here, we integrate a large amount of data from γ-secretase and its inhibitors and cancer in nearly 30 years, comb and discuss the close connection between γ-secretase and cancer, as well as the potential and problems of current GSIs in cancer treatment. We analyze the possible reasons for the failure performance of current GSIs in clinical trials, and make recommendations for future research areas.© The author(s).