Abstract
A common approach in therapeutic protein development involves employing synthetic ligands with multivalency, enabling sophisticated control of signal transduction. Leveraging the emerging concept of liquid-liquid phase separation (LLPS) and its ability to organize cell surface receptors into functional compartments, we herein have designed modular ligands with phase-separation modalities to engineer programmable interreceptor communications and precise control of signal pathways, thus inducing the rapid, potent, and specific apoptosis of tumor cells. Despite their simplicity, these “triggers”, named phase-separated Tumor Killers (hereafter referred to as psTK), are sufficient to yield interreceptor clustering of death receptors (represented by DR5) and tumor-associated receptors, with notable features: LLPS-mediated robust high-order organization, well-choreographed conditional activation, and broad-spectrum capacity to potently induce apoptosis in tumor cells. The development of novel therapeutic proteins with phase-separation modalities showcases the power of spatially reorganizing signal transduction. This approach facilitates the diversification of cell fate and holds promising potential for targeted therapies against challenging tumors.
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Data availability
The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.
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Acknowledgement
This work was supported by the National Natural Science Foundation of China (32150023). We are grateful to SLSTU-Nikon Biological Imaging Center (Center of Pharmaceutical Technology, Tsinghua University, Beijing, China) for imaging support, and Ting Wang (High Throughput Screening Core Facility, Center of Pharmaceutical Technology, Tsinghua University, Beijing, China) for SPR assays. We also thank the Tsinghua University Branch of China National Center for Protein Sciences (Beijing) and Tsinghua University Technology Center for Protein Research for the Cell Function Analyzing Facility support.
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Images were processed with Nikon NIS-Elements AR 5.20 and Adobe Illustrator CC. The fluorescence intensity was analyzed using ImageJ Fiji and the corresponding graphs were generated by GraphPad Prism 8.
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Liu, Y., Zhu, Y., Xu, W. et al. A phase separation-fortified bi-specific adaptor for conditional tumor killing. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2490-2
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DOI: https://doi.org/10.1007/s11427-023-2490-2