目前用于靶向肿瘤治疗的基于蛋白质的治疗剂表现出有限的渗透性、非特异性毒性和短的循环半衰期。尽管靶向细胞表面受体可以提高癌症选择性，但这些受体在正常细胞中也有轻微表达；因此，基于重组蛋白的治疗剂的非特异性毒性尚未消除。在这项研究中，设计了一种变构调节蛋白开关，通过变构自剪接元件和癌症标志物之间的相互作用，实现肿瘤细胞中工程化免疫毒素的细胞质重组。它可以针对缺氧癌细胞中积累的HIF-1α进行变构激活，剪接产物存在于缺氧癌细胞中而常氧细胞中不存在，选择性地杀死肿瘤细胞并减少对正常细胞的非特异性毒性。工程化的前蛋白为肿瘤靶向治疗提供了一个平台，同时提供了一种将治疗功能的激活与特定癌症标志物相结合的新颖的通用策略。变构自剪接元件是一种强大的工具，可以显着降低治疗蛋白的非特异性细胞毒性。

Protein-based therapeutic agents currently used for targeted tumor therapy exhibit limited penetrability, nonspecific toxicity, and a short circulation half-life. Although targeting cell surface receptors improves cancer selectivity, the receptors are also slightly expressed in normal cells; consequently, the nonspecific toxicity of recombinant protein-based therapeutic agents has not been eliminated. In this study, an allosteric-regulated protein switch was designed that achieved cytoplasmic reorganization of engineered immunotoxins in tumor cells via interactions between allosteric self-splicing elements and cancer markers. It can target the accumulated HIF-1α in hypoxic cancer cells and undergo allosteric activation, and the splicing products were present in hypoxic cancer cells but were absent in normoxic cells, selectively killing tumor cells and reducing nonspecific toxicity to normal cells. The engineered pro-protein provides a platform for targeted therapy of tumors while offering a novel universal strategy for combining the activation of therapeutic functions with specific cancer markers. The allosteric self-splicing element is a powerful tool that significantly reduces the nonspecific cytotoxicity of therapeutic proteins.