PurposeAlthough 60-70% of diffuse large B-cell lymphoma (DLBCL) patients can be cured with the current standard of chemotherapy and immunotherapy, the remaining patients experience treatment resistance and have poor clinical outcomes. More effective strategies are needed for the DLBCL treatment.MethodsDatabases of clinical patients were analyzed to investigate potential functions of leukocyte immunoglobulin-like receptor B1 (LILRB1) in DLBCL. Short hairpin RNAs were used for validation of in vitro and in vivo function of LILRB1 in DLBCL. RNA-seq was applied to explore potential mechanism, western blot and chromatin immunoprecipitation techniques were used to characterize the underlying signaling of CREB-SORBS3 pathway.ResultsWe found that LILRB1 was highly expressed in DLBCL cells and was adversely correlated with the overall survival of DLBCL patients. Knockdown of LILRB1 effectively inhibited the proliferation of DLBCL cells both in vitro and in vivo. Mechanistically, LILRB1 upregulated CREB/CREB phosphorylation and transactivated SORBS3 expression to maintain DLBCL cell proliferation and tumorigenicity.ConclusionIn this work, we revealed that LILRB1 was highly expressed in DLBCL cells and was negatively correlated with patient survival. Furthermore, we found that the LILRB1-CREB-SORBS3 pathway played a role in maintaining the proliferation of DLBCL cells. These data suggest that LILRB1 might be a potential target for the treatment of DLBCL.