Fat Transporter FATP2 Helps Leukemia Cells Evade CAR-T Immunotherapy

Relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL) is a major cause of cancer mortality in children and young adults. While CD19-targeted CAR-T cell therapy achieves initial remission in 80–90% of patients, roughly half relapse within a year. Understanding why CAR-T therapy fails is critical to improving outcomes. TP53 mutations, rare at initial B-ALL diagnosis but common after chemotherapy, have recently been associated with poor CAR-T responses. This study investigates the mechanisms linking TP53 loss-of-function to CAR-T resistance and identifies a targetable metabolic vulnerability.

Using isogenic B-ALL cell lines (697 and NALM-6) engineered to harbor either wildtype or mutant TP53, the researchers confirmed that TP53 mutations confer significant resistance to CD19-directed CAR-T killing in the 697 cell line. They then performed genome-wide CRISPR/Cas9 dropout screens comparing CAR-T-sensitive TP53-wildtype cells to CAR-T-resistant TP53-mutant cells. This unbiased approach identified SLC27A2—encoding Fatty Acid Transport Protein 2 (FATP2)—as a top hit specifically enriched in the resistant TP53-mutant setting. FATP2 is a membrane-bound transporter that facilitates uptake of long-chain fatty acids from the extracellular environment.

Follow-up mechanistic experiments demonstrated that TP53-mutant B-ALL cells rely heavily on exogenous lipid uptake via FATP2 to sustain fatty acid oxidation (FAO), which generates ATP and supports cell survival under immune-mediated stress. Genetic knockdown of FATP2 or pharmacological inhibition of the FAO pathway—using inhibitors of neutral lipolysis or CPT1, the rate-limiting enzyme for mitochondrial fatty acid import—significantly sensitized TP53-mutant B-ALL cells to CAR-T killing. These effects were validated in patient-derived xenograft (PDX) models, strengthening translational relevance.

Analysis of pediatric B-ALL patient datasets revealed that high SLC27A2 expression correlates with inferior survival outcomes even under conventional chemotherapy regimens, suggesting FATP2-driven lipid metabolism is a broader prognostic factor. The findings position FATP2-mediated FAO as a leukemia-intrinsic resistance mechanism that operates independently of antigen loss or CAR-T exhaustion—two previously established resistance pathways.

These results open a potential therapeutic avenue: combining CAR-T therapy with FAO inhibitors could overcome resistance in TP53-mutant B-ALL. Caveats include the predominantly in vitro and xenograft nature of the mechanistic studies, questions about FAO inhibitor tolerability in pediatric patients, and uncertainty about whether these findings extend to other B-ALL genetic subtypes beyond TP53-mutant disease.