Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics

• 成果类型: Article
• 署名作者: Rodriguez, Grayson E.; Zhao, Yang; Nishiga, Yoko; Peprah, Frank; Shen, Jiao; Abhiraman, Gita C.; Ogishi, Masato; Zhang, Chenyu; Saco, Justin; Waghray, Deepa; Serasanambati, Mamatha; Torres, Leonel; Simone, Brandon W.; Su, Leon; Wilson, Steven C.; Yang, Aerin; Sun, Qinli; Picton, Lora; Saxton, Robert A.; Bhandarkar, Vidit; Lee, Madeline J.; Andrews, Elizabeth; Jiang, Hua; Obenaus, Matthias; Yen, Michelle; Atajanova, Tavus; Blish, Catherine A.; Spranger, Stefani; Wherry, E. John; Kirane, Amanda; Ribas, Antoni; Raulet, David H.; Kalbasi, Anusha; Dougan, Stephanie K.; Dougan, Michael; Sage, Julien; Garcia, K. Christopher
• 署名单位: Stanford University; Stanford Medicine; Stanford University; Stanford University; Stanford Medicine; Stanford University; Stanford Medicine; Stanford Medicine; Stanford University; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; University of California System; University of California Berkeley; University of California System; University of California Los Angeles; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; David Geffen School of Medicine at UCLA; Stanford Medicine; Stanford University; University of Pennsylvania; Pennsylvania Medicine; University of Pennsylvania; Pennsylvania Medicine; Massachusetts Institute of Technology (MIT); Stanford Medicine; Stanford University; Chan Zuckerberg Initiative (CZI); University of Pennsylvania; Pennsylvania Medicine; University of California System; UCLA Jonsson Comprehensive Cancer Center; University of California Los Angeles; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; David Geffen School of Medicine at UCLA; Stanford Medicine; Stanford University; Stanford University; Stanford Medicine; Stanford University; Stanford Medicine; Stanford Cancer Institute; Harvard University; Harvard Medical School; Stanford Medicine; Stanford University; Stanford Medicine; Stanford University; Howard Hughes Medical Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adx9954
• 发表日期: 2026-05-14
• 页码: eadx9954
• 关键词: cd8(+) t-cells; DOSE INTERLEUKIN-2; in-vivo; receptor; expression; il-2; cytokines; immunosuppression; autoimmune; DISCOVERY

摘要

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.