OBJECTIVES: Classical Hodgkin lymphoma (cHL) is identified by the appearance of Hodgkin and Reed-Sternberg cells. and are deubiquitinating enzymes involved in negatively regulating NF-κB-mediated immune response. Vincristine (Vinc) and doxorubicin (Dox) are classical antitumor drugs, in which Dox serves a key role in chemotherapy against cHL and Vinc induces disruption of microtubule function that inhibits mitosis of cancer cells. Little is known about the roles of in regulating macrophage function from cHL patients upon treatment with Vinc or Dox. This study, therefore, asked whether expression affects function of macrophages in cHL cases. MATERIALS AND METHODS: Macrophages from cHL patients differentiated from bone marrow cells were exposed to Vinc or Dox. Gene expression levels were determined by real time-qPCR, cell maturation, apoptosis and phagocytosis by flow cytometry, and cytokine release by ELISA. RESULTS: Dox induced maturation, apoptosis, and phagocytosis of macrophages in cHL cases. Moreover, the percentage of CD68CD40, but not CD68CD86 cells as well as levels of IL-1β were further enhanced when exposed to siRNA, whereas the absence of unaltered macrophage function in cHL patients. Importantly, the increased numbers of -sensitive CD68CD40 and Annexin VPI cells as well as enhanced levels of caspase 3 were abolished in the presence of mTOR inhibitor Everolimus. CONCLUSION: The present study indicates that Dox-induced macrophage maturation and apoptosis are dependent on expression through mTOR signaling. Moreover, inhibition of Dox-induced macrophage maturation in the patients with low A20 expression by Everolimus might represent a promising therapy for -sensitive cHL cases.