Abstract We have previously shown that breast cancer generates regulatory B cells (tBregs) to convert Tregs and thereby to enable its metastasis. Thus, we decided to deplete tBregs using aCD20 antibody, a counterpart of the FDA approved strategy for the treatment of B cell malignancies (Rituximab). To our surprise, when tumor bearing mice were treated with αCD20 antibody, tumor progression was accelerated leading to increased lung metastasis. Thus, we hypothesized that tBregs may not be targeted by the antibody due to their low expression of CD20. Indeed, we found that B cell during their conversion to tBregs, downregulate their CD20 expression. Thus, tumor bearing mice treated with aCD20 antibody had enriched amounts of tBregs. We provide evidence that CD20 cannot be a target for the depletion of tBregs, explaining the failure of Rituximab to improve clinical outcomes in solid tumors. Instead, we developed an alternative strategy by in vivo targeting CpG through CXCR5 expressed by tBregs. We show that BLCArp-CpG inactivates tBregs, thereby reversing tumor metastasis. Taken together, suppressive B cells need to be controlled in solid tumors.