Targeted therapies have considerably improved the survival rate of B-cell non-Hodgkin lymphoma (B-NHL) patients in the last decade; however, most subtypes remain incurable. TG-1801, a bispecific antibody that targets CD47 selectively on CD19+ B-cells, is under clinical evaluation in relapsed/refractory B-NHL patients either as a single-agent or in combination with ublituximab, a CD20 antibody, which is also being combined with the PI3Kδ/CK1e inhibitor, umbralisib (“U2”-regimen). In this study, we demonstrated that TG-1801 potentiates ublituximab-mediated antibody-dependent cell death (ADCC) and antibody-dependent cell phagocytosis (ADCP), leading to an additive anti-tumour effect of the TG-1801/U2 combination in B-NHL co-cultures. Accordingly, in a B-NHL xenotransplant model, the triplet achieved a 93% tumour growth inhibition, with 40% of the animals remaining tumour-free 35 days after the last dosing. Transcriptomic analysis further uncovered the upregulation of the G protein-coupled receptor, GPR183, as a crucial event associated with TG-1801/U2 synergism, while pharmacological blockade or genetic depletion of this factor impaired ADCP initiation, as well as cytoskeleton remodelling and cell migration, in B-NHL cultures exposed to the drug combination. Thus, our results set the preclinical rationale and support a combination strategy of TG-1801 with PI3Kδ- and CD20-targeting agents in patients with B-NHL. Overall design: We used RNA-seq to uncover the mechanisms underlying the triplet combination (TG-1801 + U2) activity in Burkitt lymphoma. RNA-seq was performed in two Burkitt lymphoma (BL) cell lines (Daudi and Raji), two BL primary samples subjected to the following treatments for 24h: TG-1801 (10 ng/mL ), U2 (umbralisib 1 µM + ublituximab 10 µg/mL) and the triplet combinationand. Additionally we also included two representative bulk Raji xenografts from the following treatment arms : TG-1801 (5 mg/kg, qw), Ublituximab (5 mg/kg, qw) + Umbralisib (150 mg/kg, bid), the triplet (U2 + TG-1801).