Ponatinib inhibits LCK and PI3K signaling and promotes CD8<sup>+</sup> T stem cell memory cell development.
basic_science · Level V
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- Record sourced from PubMed, PMID 41946709.
- Also identified by DOI 10.1038/s41467-026-71375-2.
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Abstract
CD8<sup>+</sup> T stem cell memory (T<sub>SCM</sub>) cells show clinical promise for cancer immunotherapy, but T<sub>SCM</sub> 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<sup>+</sup> T<sub>SCM</sub> cell differentiation. Mechanistically, stable and sustained, but not intermittent, inhibition of the LCK and PI3K pathways is essential for CD8<sup>+</sup> T<sub>SCM</sub> 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) T<sub>SCM</sub> cells by reducing CAR T cell exhaustion, resulting in durable antitumor efficacy. Our results thus implicate ponatinib as therapeutic immunomodulator, inducing T<sub>SCM</sub> cells for improved antitumor T cell activity.