2026/04/07 by Yuki Okuhiro, Sachiko Ito, Keisuke Watanabe +10 · 1 voice
Medicine · #Acute Lymphoblastic Leukemia research #CAR-T cell therapy research #Chronic Myeloid Leukemia Treatments
paper · doi:10.1038/s41467-026-71375-2
openalex publication_date 2026/04/07 · openalex created_date 2026/04/08 · openalex updated_date 2026/07/29
CD8+ T stem cell memory (TSCM) cells show clinical promise for cancer immunotherapy, but TSCM cell generation in clinical settings requires further optimization. Ponatinib is a tyrosine kinase inhibitor primarily targeting BCR-ABL1 and used for the treatment of chronic myeloid leukemia. Here, we investigate the effect of ponatinib on T cell activation and differentiation. Acting off-target, ponatinib inhibits LCK and PI3K signaling to enhance the transcriptional functions of TCF7 and FOXO1, thereby promoting CD8+ TSCM cell differentiation. Mechanistically, stable and sustained, but not intermittent, inhibition of the LCK and PI3K pathways is essential for CD8+ TSCM cell induction. In mouse tumor models, ponatinib treatment exhibits antitumor efficacy alone and in combination with PD-1 blockade. Furthermore, ponatinib increases chimeric antigen receptor (CAR) TSCM cells by reducing CAR T cell exhaustion, resulting in durable antitumor efficacy. Our results thus implicate ponatinib as therapeutic immunomodulator, inducing TSCM cells for improved antitumor T cell activity. As a tyrosine kinase inhibitor targeting BCR-ABL, ponatinib has been used to treat chronic myeloid leukemia. Here, the authors identify LCK and PI3K signaling as additional ponatinib targets, with ponatinib inducing CD8+ T stem cell memory cells, thereby boosting immune checkpoint blockade and CAR T cell therapy.