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While CD19-directed chimeric antigen receptor T cell (CAR-T) therapy offers promise, high rates of long-term failure underscore the need to understand resistance mechanisms. Our studies found p53 inactivation promotes CAR-T resistance in human pre-B-ALL cell lines. Through genome-wide CRISPR\/Cas9 screening of CAR-sensitive\n                    <jats:italic>TP53<\/jats:italic>\n                    -wildtype and CAR-resistant\n                    <jats:italic>TP53<\/jats:italic>\n                    -mutated CD19\u2009+\u2009B-ALL cell lines, we found the Fatty Acid Transport Protein 2 (FATP2, encoded by\n                    <jats:italic>SLC27A2<\/jats:italic>\n                    ) is a leukemia-intrinsic mechanism of CAR-T resistance in\n                    <jats:italic>TP53<\/jats:italic>\n                    -mutant B-ALL. High\n                    <jats:italic>SLC27A2<\/jats:italic>\n                    expression in pediatric B-ALL patients correlate with worse survival outcomes following conventional chemotherapy. Using B-ALL cell lines and patient-derived xenografts, we show that FATP2-expressing\n                    <jats:italic>TP53<\/jats:italic>\n                    -mutant B-ALL resistance to CAR-T is dependent on exogenous lipid uptake to fuel fatty acid oxidation (FAO) and cell survival, which can be pharmacologically targeted through inhibition of neutral lipolysis and CPT1. These findings identify FATP2-mediated fatty acid uptake and downstream FAO as a potential target to improve existing CAR-T efficacy in human B-ALL.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-03030-0","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T08:39:12Z","timestamp":1782808752000},"page":"1763-1777","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["FATP2-mediated lipid metabolism enhances chimeric antigen receptor T-cell therapy resistance in B-cell acute lymphoblastic leukemia"],"prefix":"10.1038","volume":"40","author":[{"given":"Clarissa","family":"Garcia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaylyn 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