{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T13:11:10Z","timestamp":1780060270320,"version":"3.54.0"},"reference-count":121,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Adoptive T cell therapies can deliver curative responses for refractory patients with B cell malignancies, yet clinical activity in solid tumors remains inconsistent. Tumor-intrinsic barriers dominating this inconsistency include the immunosuppressive solid tumor microenvironment (TME) imposing chronic inhibitory cues to T cells and the scarcity of patient-shared and uniformly expressed tumor-restricted antigens for T cells to target. CRISPR-based forward genetics screens enable mapping of the functional genome regulating T cell anti-tumor activity. Here, we review recent insights from pooled CRISPR knockout screens in T cells to define convergent targets and pathways regulating T cell anti-tumor function and align the pharmacology of engineered T cells with sequential barriers they encounter within the TME. We additionally propose a framework for CRISPR screen-enabled target prioritization and present an example of how these principles can be applied to the functional enhancement of T cells through TIL (Tumor Infiltrating Lymphocyte) therapy, which utilizes a patient\u2019s personalized immune response against solid tumor antigens.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1839064","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T12:23:31Z","timestamp":1780057411000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CRISPR-screen informed engineered T cell therapies"],"prefix":"10.3389","volume":"17","author":[{"given":"Karrie","family":"Wong","sequence":"first","affiliation":[{"name":"KSQ Therapeutics","place":["Lexington, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conor","family":"Calnan","sequence":"additional","affiliation":[{"name":"KSQ 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