Synergistic Anti-Tumor Effect of Chidamide and Linperlisib on Natural Killer/T-Cell Lymphoma by Inhibiting PI3K/AKT/mTOR Pathway.

Natural killer/T-cell lymphoma (NKTCL) is an aggressive lymphoma subtype with limited treatment options, especially for relapsed or refractory patients. Chidamide, a histone deacetylase inhibitor, and linperlisib, a phosphatidylinositol-3-kinase (PI3K) inhibitor, have shown promise in treating peripheral T-cell lymphoma, but their effects on NKTCL are less explored. In this study, the therapeutic efficacy and mechanisms of combining chidamide and linperlisib in the treatment of NKTCL were investigated. Three human NKTCL cell lines (NKYS, KHYG1, and YT) were used to assess the effects of chidamide and linperlisib on cell proliferation, apoptosis, and the cell cycle. RNA-seq and Western blot assays were employed to uncover the underlying mechanisms, and a YT xenograft mouse model was used for in vivo validation. Both chidamide and linperlisib exhibited dose- and time-dependent anti-tumor effects, and their combination enhanced efficacy, reduced cell viability, and increased apoptosis. This combination induced G2/M cell cycle arrest. Transcriptomic, Western blot, and immunohistochemical analysis revealed significant inhibition of the PI3K/AKT/mTOR pathway, which correlated with upregulation of the tumor suppressor PRDM1. These findings were confirmed in the YT xenograft model. In conclusion, the combination of chidamide and linperlisib has synergistic anti-tumor effects on NKTCL, which are mediated through inhibition of the PI3K/AKT/mTOR pathway, suggesting a promising therapeutic strategy for NKTCL management.