Abstract: Background and purpose: With the clinical application of sequential L-asparaginase-containing chemotherapy and radiotherapy as well as immune checkpoint inhibitors, both rates of response and progression-free survival of patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTCL) have dramatically improved. However, a considerable number of advanced-stage patients become relapsed/refractory cases. It has been found that quinacrine, as an antiparasitic small molecular compound, could induce cell cycle arrest and apoptosis in different types of tumor cells in vitro including hematologic malignancies, which might be a promising novel antineoplastic pharmacotherapy. The present study aimed to explore the possible effects of quinacrine on ENKTCL cells and its potential mechanisms. Methods: The ENKTCL cell line SNK6 and NK92 cells (provided by Department of Hematology, Xinhua Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University and Shanghai Institute of Hematology) were treated with different concentrations of quinacrine. The proliferations of SNK6 and NK92 cells were evaluated through cellular morphology and cell counting kit (CCK-8) assay. Meanwhile, flow cytometry was used to analyze changes of cell cycle distribution and apoptotic rate as well as mitochondrial transmembrane potential (ΔΨm) and intracellular reactive oxygen species (ROS) level. Furthermore, Western blot assay was applied to detect expression levels of autophagy modulator LC3B and P70. Results: After treating with quinacrine for 48 h, the growth inhibition rates of SNK6 and NK92 cells reached to (47.08±2.19)% and (30.46±7.95)% respectively, which were significantly higher compared with control group ［(11.85±1.89)% and (10.08±2.01)%; P<0.05］. The apoptotic rates of SNK6 and NK92 cells in quinacrine groups after 24 h were (86.45±6.54)% and (76.5±10.8)% respectively, which were significantly higher compared with control group［(3.3±3.24)% and (2.64±1.67)%; P<0.05］. It was also shown that quinacrine could induce S-phase cell cycle arrest in SNK6 and NK92 cells, though little influence on mitochondrial ΔΨm was observed. Furthermore, quinacrine could trigger elevation of ROS level and inhibition of P70 phosphorylation as well as up-regulate expression of LC3B in these cells. Conclusion: Quinacrine could induce proliferation inhibition and apoptosis in ENKTCL cells, which might be mediated by intracellular ROS and simultaneous suppression of mTOR signaling pathway to trigger cell autophagy.