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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\n                    <jats:italic>SAFB<\/jats:italic>\n                    ,\n                    <jats:italic>KHDRBS1<\/jats:italic>\n                    ,\n                    <jats:italic>MYC<\/jats:italic>\n                    ,\n                    <jats:italic>CD44<\/jats:italic>\n                    ,\n                    <jats:italic>WNT3A<\/jats:italic>\n                    ,\n                    <jats:italic>WNT1<\/jats:italic>\n                    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\u2013in situ Perturb-seq show that the hits converge on shared cell-autonomous and intercellular mechanisms, map gene\u2013environment 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.\n                  <\/jats:p>","DOI":"10.1038\/s41588-026-02561-7","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T09:04:26Z","timestamp":1775552666000},"page":"841-853","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["High-content CRISPR activation screens identify synthetically lethal RNA-based mechanisms to sensitize cancer cells to targeted T cell cytotoxicity"],"prefix":"10.1038","volume":"58","author":[{"given":"Reece Villarin","family":"Akana","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeehyun","family":"Yoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4416-0475","authenticated-orcid":false,"given":"Olivia","family":"Laveroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2080-5450","authenticated-orcid":false,"given":"Chang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Min","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4037-386X","authenticated-orcid":false,"given":"Livnat","family":"Jerby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"2561_CR1","first-page":"17","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel, R. 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