Nature子刊：我国学者开发新型蛋白靶向降解技术——FRTAC，高效降解膜蛋白

Core Viewpoint - The article discusses the development and potential of protein-targeting degradation technologies, particularly focusing on PROTAC and the newly developed FRTAC, which targets membrane proteins for degradation, showing promise in cancer treatment [1][9]. Group 1: PROTAC and Related Technologies - PROTAC (Proteolysis Targeting Chimeras) utilizes ubiquitin ligases to promote the degradation of pathogenic proteins, making previously "undruggable" proteins viable therapeutic targets [1]. - Several PROTAC drugs are in clinical trials, with Vepdegestrant targeting estrogen receptors recently releasing phase 3 trial results, indicating a potential market entry soon [1]. - Other technologies like LYTAC (Lysosome-Targeting Chimeras) and AUTAC (Autophagy-Targeting Chimeras) have been developed, with LYTAC focusing on secreted and membrane proteins, which constitute about 40% of the human proteome [1]. Group 2: FRTAC Development - A new platform called FRTAC (Folate Receptor-Targeting Degraders) has been developed, which targets membrane proteins for lysosomal degradation using the folate receptor α (FRα) as a transport receptor [3][5]. - FRTAC shows selective internalization in cancer cells overexpressing FRα, effectively transporting target proteins to lysosomes for degradation [5]. - The optimized FRTAC demonstrates sub-nanomolar efficacy in clearing membrane proteins, with its effectiveness dependent on FRα expression and lysosomal activity [5]. Group 3: Applications and Efficacy - The research team constructed FRTACs targeting EGFR and PD-L1, with FR-Ctx inhibiting cancer cell proliferation and FR-Atz enhancing T cell-mediated cytotoxicity against tumor cells [7]. - In mouse models of prostate cancer and humanized melanoma, FR-Atz exhibited strong in vivo PD-L1 targeting degradation efficiency, reprogramming the tumor microenvironment from immunosuppressive to immunostimulatory, outperforming traditional antibody drugs [8]. - Overall, FRTAC can target tumor sites with high affinity and sub-nanomolar activity to degrade membrane proteins, indicating a promising application in cancer therapy [9].