Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics
- 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
2026-02-19
Cytokines dimerize two receptor chains to activate Janus kinases and STAT transcription factors that regulate immune cells but 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 co-activated pSTAT5 and pSTAT3 signatures distinct from natural cytokines, by assembling trimeric combinations of Interleukin-2 (IL-2), Interleukin-10 (IL-10), and Interleukin-21 (IL-21) receptors. In pre-clinical 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 pre-clinical 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.