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Signal Transduct. Target. Ther., Apr 10 2026, 11 (1) 129 | https://doi.org/10.1038/s41392-026-02623-6 Rapid CAR screening and circRNA-driven CAR-NK cells for persistent shed-resistant immunotherapy

Joo-Yoon Chung^1,2, Jisu Hong³, Su-Min Yee¹, Hye Won Lim⁴, Dahye Lee⁵, Sangwon Yoon⁶, Seung-Hwan Lee^7,8, Yujin Jung³, Seung Hun Shin^1,9, Song Cheol Kim¹⁰, Chang-Han Lee^3,4,5,11,12* and Mihue Jang^1,2,13*

¹Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea;
²KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea;
³Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Republic of Korea;
⁴Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Republic of Korea;
⁵Department of Pharmacology, SeoulNational University College of Medicine, Seoul 03080, Republic of Korea;
⁶Corporate Research & Development Center, UCI Therapeutics, Seoul 04784, Republic of Korea;
⁷Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada;
⁸Ottawa Institute of Systems Biology, Faculty of Medicine and Centre for Infection, Immunity, and Inflammation, Faculty of Medicine, University of Ottawa, Ontario K1N 6N5, Canada;
⁹Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea;
¹⁰Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 05505 Seoul, Republic of Korea;
¹¹BK21 FOUR Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Republic of Korea;
¹²Wide River Institute of Immunology, Seoul National University, Hongcheon 25159, Republic of Korea and
¹³Division of Bio-Medical Science and Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Republic of Korea

^*Correspondence: Chang-Han Lee or Mihue Jang
These authors contributed equally: Joo-Yoon Chung, Jisu Hong.

Abstract

Chimeric antigen receptor (CAR)-based immunotherapies against solid tumors face two major hurdles, the "decoy effect" of shedding antigens that sequester CARs, and the limited persistence of immune effectors within the immunosuppressive tumor microenvironment. Here, we present a mechanistic approach to overcome these barriers by integrating a physiologically relevant screening platform with circular RNA (circRNA) engineering. Unlike conventional screens using immortalized cell lines, we performed rapid functional screening directly in human primary natural killer (NK) cells to identify a novel scFv, CLMS10. Structural modeling revealed that CLMS10 targets a membrane-proximal epitope that overlaps the proteolytic cleavage site, thereby evading inhibition by soluble mesothelin (solMSLN). Furthermore, we demonstrated that circRNA-mediated CAR expression, when codelivered with interleukin-21 (IL-21), confers sufficient stability to withstand the continuous antigen shedding induced by cancer-associated fibroblasts (CAFs), resulting in reduced CAR downregulation. In an in vivo metastatic pancreatic cancer model, IL-21-augmented circCAR-MS10-NK cells exhibited potency comparable to that of lentivirally engineered CAR-NK cells while offering superior manufacturability. Overall, this study establishes a paradigm for generating shed-resistant CAR therapeutics through the strategic integration of epitope-specific functional selection and enhanced RNA stability.

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