该课题组人员设计了“Trikines”，以迫使在细胞表面顺式形成三链细胞因子受体复合物，从而诱导定制的STAT转录信号程序。三因子通过组装白介素-2 （IL-2）、IL-10和IL-21受体的三聚体组合，共同激活了与天然细胞因子不同的STAT5 （pSTAT5）和pSTAT3信号的磷酸化。在临床前模型中，基于IL-2的三因子抑制了T细胞的终末分化，促进了肿瘤的干性，并增强了肿瘤控制的持久性，而没有明显的毒性。一种基于IL-10的三因子诱导免疫浸润到免疫原性较差的肿瘤中，在小细胞肺癌和胰腺癌的临床前模型中显示出疗效。三因子消除了细胞工程对STAT特征进行细胞化的需要，并且可能具有免疫治疗的潜力。
研究人员表示，细胞因子二聚体化两条受体链来激活Janthem激酶和调节免疫细胞的信号转导和转录激活因子（STAT）转录因子，但它们具有治疗作用。
附：英文原文
Title: Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics
Author: Grayson E. Rodriguez, Yang Zhao, Yoko Nishiga, Frank Peprah, Jiao Shen, Gita C. Abhiraman, Masato Ogishi, Chenyu Zhang, Justin Saco, Deepa Waghray, Mamatha Serasanambati, Leonel Torres, Brandon W. Simone, Leon Su, Steven C. Wilson, Aerin Yang, Qinli Sun, Lora Picton, Robert A. Saxton, Vidit Bhandarkar, Madeline J. Lee, Elizabeth Andrews, Hua Jiang, Matthias Obenaus, Michelle Yen, Tavus Atajanova, Catherine A. Blish, Stefani Spranger, E. John Wherry, Amanda Kirane, Antoni Ribas, David H. Raulet, Anusha Kalbasi, Stephanie K. Dougan, Michael Dougan, Julien Sage, K. Christopher Garcia
Issue&Volume: 2026-05-14
Abstract: Cytokines dimerize two receptor chains to activate Janus kinases and signal transducer and activator of transcription (STAT) transcription factors that regulate immune cells, but they have therapeutic liabilities. We engineered “Trikines” to compel cis formation of three-chain cytokine receptor complexes at the cell surface that induce bespoke STAT transcriptional signaling programs. Trikines coactivated phosphorylation of STAT5 (pSTAT5) and pSTAT3 signatures distinct from natural cytokines by assembling trimeric combinations of interleukin-2 (IL-2), IL-10, and IL-21 receptors. In preclinical models, an IL-2–based Trikine restrained terminal differentiation of T cells, promoted stemness, and enhanced durability of tumor control without observable toxicity. An IL-10–based Trikine induced immune infiltration into poorly immunogenic tumors, showing efficacy in preclinical models of small cell lung cancer and pancreatic cancer. Trikines obviate the need for cell engineering to customize STAT signatures and may hold potential for immunotherapy.
DOI: adx9954
Source: https://www.science.org/doi/10.1126/science.adx9954