Lipid Metabolism and CAR-T Resistance in B-ALL
Garcia C, Lyons KU, Contreras JG, et al. FATP2-Mediated Lipid Metabolism Enhances Chimeric Antigen Receptor T-Cell Therapy Resistance in B-Cell Acute Lymphoblastic Leukemia. Leukemia. 2026.
Recent study findings may offer clues into what kind of scenarios support or undermine chimeric antigen receptor T-cell (CAR-T) therapy for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). While high relapse rates are often attributed to short-lived CAR T-cell persistence and other mechanisms, a growing body of evidence points to leukemia-intrinsic factors — such as TP53 mutations — as another potential culprit. Researchers working on the current study compared CAR-sensitive TP53-wildtype and CAR-resistant TP53-mutated CD19+ B-ALL cell lines, noting a correlation between lipid metabolism and CAR-T resistance. Specifically, Fatty Acid Transport Protein 2 mediates CAR-T resistance in TP53-mutant B-ALL. Exogenous lipid uptake is necessary to support fatty acid oxidation and cell survival that allow B-ALL to resist the cytotoxic effects of CD19-directed CAR-T therapy. However, the researchers suggest there is an opportunity to pharmacologically inhibit this process and thereby enhance CAR-T efficacy in B-ALL.