Gamma Secretase Inhibitors in Cancer

Gamma secretase inhibitors (GSIs), for Alzheimer's disease treatment, have been repurposed as anticancer agents because they inhibit receptor cleavage. Preclinical studies suggested that GSIs effectively promote the differentiation and apoptosis of cancer stem-like cells while obstructing epithelial-to-mesenchymal transition and increasing sensitivity to conventional chemotherapy and radiotherapies. However, their clinical application remains limited, as GSIs have shown minimal efficacy in the majority of solid tumors, with significant exceptions including central nervous system malignancies and desmoid tumors. It highlights several unresolved questions, including their overall impact on anticancer immune responses and whether targeting tumor-intrinsic compensatory pathways would be necessary for achieving optimal results. Advancing our understanding of GSI mechanisms is critical for effectively integrating these inhibitors into combination therapies and addressing Notch-dependent cancers. This review aims to provide a comprehensive overview of GSI mechanisms, analyze their clinical effects thus far, and propose future research directions. It emphasizes the importance of evaluating GSIs' effects on immune responses in cancer patients and overcoming tumor-intrinsic resistance to unlock their full therapeutic potential, paving the way for more effective combinatorial strategies in oncology.