Core Viewpoint - The article discusses a novel cancer treatment strategy called "Decaging-to-Ligation" (D2L), which enables precise recruitment of proteins or immune cells to tumor sites, significantly inhibiting tumor growth while minimizing systemic toxicity [3][12]. Group 1: Research Findings - The study successfully synthesized proteolysis-targeting chimeras (PROTAC) in tumor-localized concentrations sufficient for effective target protein degradation, leading to a 14.8-fold increase in T cell activation levels [2][10]. - The D2L strategy effectively overcomes On-target Off-tumor (OTOT) toxicity, a major barrier for therapies like PROTAC and T cell-mediated immunotherapy [5][12]. - The research team demonstrated the feasibility of the D2L strategy by achieving selective imaging of FAP-positive cells and successfully degrading the target protein BRD4 in tumors with minimal toxicity to the small intestine [10][12]. Group 2: Technological Innovations - The D2L strategy represents an innovative approach in the intersection of chemical biology and drug discovery, facilitating tumor-selective reactions that can induce proximity effects between proteins and cells [7][12]. - The study highlights the potential of bioorthogonal chemistry in achieving selective drug release at tumor sites, bridging the gap between bioorthogonal connection technology and tumor-selective regulation [6][12]. Group 3: Implications for Cancer Treatment - The D2L strategy is positioned as a promising platform for precise cancer treatment, aiming to activate therapeutic assemblies in vivo and address critical limitations of proximity-mediated cancer therapies [12].

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].

| nature | | | | | --- | --- | --- | --- | | medicine | | 30 | | | | | | 385 2 | | 创刊30周年,医学的未来与挑战 | | | | | celebrating | | | | | 30 | | | | | vears | | | | | | Rober Referr 111 : " | HE EFF | | 撰文丨王聪 编辑丨王多鱼 排版丨水成文 沿 浓度梯度被动扩散穿过细胞的脂质双层膜，被广泛认为是小分子药物吸收的主要机制，尽管已发现少数 转运蛋白能促进营养物质和化学物质的扩散，但其作用有限。脂溶性小分子 （分子量 ≤ 500 道尔顿） 更 有可能通过被动扩散穿过细胞膜进入细胞内，而较大的分子 （例如分子量 > 800 道尔顿） 无法被动穿过 质膜，这限制了小分子药物能够作用的范围。 但实际上，也有许多大分子药物是能够被细胞吸收的，其中最典型的是 蛋白靶向降解嵌合体 （ PROTAC） ，这是一种异双功能化合物，由一个 （或多个） 靶向目标蛋白的配体和一个 E3 泛素连接酶 配体通过连接子 （linker） 连接而成。PROT ...