Ponatinib inhibits LCK and PI3K signaling and promotes CD8⁺ T stem cell memory cell development

CD8⁺ T stem cell memory (T_SCM) cells show clinical promise for cancer immunotherapy, but T_SCM 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⁺ T_SCM cell differentiation. Mechanistically, stable and sustained, but not intermittent, inhibition of the LCK and PI3K pathways is essential for CD8⁺ T_SCM 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_SCM cells by reducing CAR T cell exhaustion, resulting in durable antitumor efficacy. Our results thus implicate ponatinib as therapeutic immunomodulator, inducing T_SCM cells for improved antitumor T cell activity.