Abstract: OBJECTIVE To investigate the inhibitory effect of lenalidomide on PD1/PD-L1 to enhance lymphocyte killing effect of HepG2. METHODS Human lymphocytes were co-cultured with HepG2, flow cytometry was used to detect the apoptosis of HepG2, CCK-8 detected HepG2 activity, Western blot was used to detect PD-L1/PD-1 expression. The expression of IL-2, IL-12 and TNF-α was detected by Elisa method. To construct mouse model of HepG2, after lenalidomide intervention, calculated the tumor inhibition rate, Western blot was used to detect the expression of PD-1 and PD-L1 in mouse carcinoma, qPCR was used to detect the mRNA expression of IL-2, IL-12 and TNF-α in cancer tissues. RESULTS Lenalidomide could increase the ability of lymphocytes to kill HepG2, HepG2 apoptosis rate was significantly increased, PD-1 and PD-L1 expression decreased, IL-2, IL-12 and TNF-α expression were increased. Lenalidomide had a significant tumor inhibitory effect on mice, it could reduce the expression of PD-1 and PD-L1 in tumor tissue, and increased IL-2, IL-12 and TNF-α mRNA expression. CONCLUSION The anti-tumor effect of lenalidomide is related to its immune regulation, Lenalidomide can inhibit PD-1/PD-L1 to enhance lymphocyte killing of HepG2。