FATP2-mediated lipid metabolism enhances chimeric antigen receptor T-cell therapy resistance in B-cell acute lymphoblastic leukemia

作者：Clarissa Garcia, Kaylyn U. Lyons, Julian Grandvallet Contreras, Tian Liu, Alexis J. Donnelly, Amanda J. Novak, Amy Argabright, Colin C. Anderson, Abby Grier, Sabrina Smith, Joshua Michlin, Jesutomisin Olusoji, Railey G. Mikeska, Xin Zhou, Huimin Geng, Jeremy Rahkola, Hiten N. Patel, Jeffrey G. Jacot, Markus Müschen, Angelo D’Alessandro, John E. Dick, Ilaria Iacobucci, Charles G. Mullighan, Julie A. Reisz, Tzu Phang, M. Eric Kohler, Matthew T. Witkowski · 发表于：Leukemia · 年份：2026 · DOI：10.1038/s41375-026-03030-0 · 研究领域：Acute Lymphoblastic Leukemia research、CAR-T cell therapy research、Immune Cell Function and Interaction

Relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) remains a leading cause of cancer-related death in children and young adults. 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 TP53-wildtype and CAR-resistant TP53-mutated CD19 + B-ALL cell lines, we found the Fatty Acid Transport Protein 2 (FATP2, encoded by SLC27A2) is a leukemia-intrinsic mechanism of CAR-T resistance in TP53-mutant B-ALL. High SLC27A2 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 TP53-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.