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<p>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.</p>

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Rapid CAR screening and circRNA-driven CAR-NK cells for persistent shed-resistant immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Joo-Yoon Chung,
  • Jisu Hong,
  • Su-Min Yee,
  • Hye Won Lim,
  • Dahye Lee,
  • Sangwon Yoon,
  • Seung-Hwan Lee,
  • Yujin Jung,
  • Seung Hun Shin,
  • Song Cheol Kim,
  • Chang-Han Lee,
  • Mihue Jang

摘要

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.