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<p>T cells recognize their target cells through the T cell receptor (TCR). Combining gain-of-function, single-cell and optical high-content screens, we identified RNA-based mechanisms that selectively sensitize target cells to TCR-specific T cell cytotoxicity. First, CRISPR activation screens in melanoma cells identify functionally diverse regulators of TCR-specific cytotoxicity, including <i>SAFB</i>, <i>KHDRBS1</i>, <i>MYC</i>, <i>CD44</i>, <i>WNT3A</i>, <i>WNT1</i> and others. Expressing sensitizing hits in cancer and virally infected cells restores TCR-specific cytotoxicity. Next, we developed in situ Perturb-seq for optical pooled genetic screens with in situ detection of perturbations and spatial transcriptomic readouts. Perturb-seq and in vivo–in situ Perturb-seq show that the hits converge on shared cell-autonomous and intercellular mechanisms, map gene–environment interactions and reveal that Wnt ligands activate T cells. Introducing a scalable approach to decode gene function at the cell and tissue level, the study uncovered context-specific gene functions to restore targeted T cell-based elimination of dysfunctional cells via synthetically lethal, RNA-based interventions.</p>

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High-content CRISPR activation screens identify synthetically lethal RNA-based mechanisms to sensitize cancer cells to targeted T cell cytotoxicity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月7日

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  • Reece Villarin Akana,
  • Jeehyun Yoe,
  • Olivia Laveroni,
  • Chang Sun,
  • Young-Min Kim,
  • Livnat Jerby

摘要

T cells recognize their target cells through the T cell receptor (TCR). Combining gain-of-function, single-cell and optical high-content screens, we identified RNA-based mechanisms that selectively sensitize target cells to TCR-specific T cell cytotoxicity. First, CRISPR activation screens in melanoma cells identify functionally diverse regulators of TCR-specific cytotoxicity, including SAFB, KHDRBS1, MYC, CD44, WNT3A, WNT1 and others. Expressing sensitizing hits in cancer and virally infected cells restores TCR-specific cytotoxicity. Next, we developed in situ Perturb-seq for optical pooled genetic screens with in situ detection of perturbations and spatial transcriptomic readouts. Perturb-seq and in vivo–in situ Perturb-seq show that the hits converge on shared cell-autonomous and intercellular mechanisms, map gene–environment interactions and reveal that Wnt ligands activate T cells. Introducing a scalable approach to decode gene function at the cell and tissue level, the study uncovered context-specific gene functions to restore targeted T cell-based elimination of dysfunctional cells via synthetically lethal, RNA-based interventions.