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In particular, T cells exposed to nutrient deprivation and hypoxia upregulate autophagy, a lysosomal degradation pathway that negatively regulates effector responses. Here, we used CRISPR-Cas9 to target a folate receptor alpha (\u03b1FR) CAR expression cassette into the locus of the essential autophagy gene\n                  <jats:italic>ATG5<\/jats:italic>\n                  , thereby generating autophagy-deficient CAR-T cells in a single editing step.\n                <\/jats:p>\n                <jats:p>\n                  Targeted metabolite profiling revealed that deletion of\n                  <jats:italic>ATG5<\/jats:italic>\n                  induced widespread metabolic reprogramming characterized by increased glucose and amino acid uptake. Functionally,\n                  <jats:italic>ATG5<\/jats:italic>\n                  -knockout CAR-T cells maintained high cytolytic activity when assayed in patient-derived ascites\n                  <jats:italic>in vitro<\/jats:italic>\n                  , and exhibited superior and long-lasting tumor control against ovarian tumors\n                  <jats:italic>in vivo<\/jats:italic>\n                  .\n                <\/jats:p>\n                <jats:p>\n                  Taken together, our results suggest that deletion of\n                  <jats:italic>ATG5<\/jats:italic>\n                  metabolically primes CAR-T cells for enhanced cytotoxicity in immune-suppressive conditions, thereby improving the therapeutic potential of \u03b1FR CAR-T cells for ovarian cancer immunotherapy.\n                <\/jats:p>","DOI":"10.1101\/2025.10.09.681473","type":"posted-content","created":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:50:16Z","timestamp":1760147416000},"source":"Crossref","is-referenced-by-count":1,"title":["Autophagy disruption primes CAR-T cell metabolism for sustained rejection of ovarian tumors"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4281-7193","authenticated-orcid":false,"given":"Gillian A","family":"Carleton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Levesque","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren G","family":"Zacharias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao San","family":"Patricio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"Sutcliffe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter H","family":"Watson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph J","family":"DeBerardinis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3889-9563","authenticated-orcid":false,"given":"Yannick","family":"Doyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian J","family":"Lum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101409251389000_2025.10.09.681473v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00754-1"},{"key":"2025101409251389000_2025.10.09.681473v1.2","doi-asserted-by":"crossref","unstructured":"Daei Sorkhabi A , Mohamed Khosroshahi L , Sarkesh A , Mardi A , Aghebati-Maleki A , Aghebati-Maleki L , et al. 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