Lymph node microenvironment remodeling unlocks local antibody-mediated B cell depletion.

Lymph nodes (LNs) can act as reservoirs in CD20+ B cell malignancies and autoimmune diseases. Although anti-CD20 monoclonal antibodies (mAbs) have substantially improved patient outcomes, relapse and disease progression remain frequent, underscoring critical limitations that constrain their full therapeutic potential. Here, we reveal that the LN microenvironment is an important modulator of anti-CD20 mAb efficacy. Within LNs, malignant B cells can exhibit a sessile, tissue-retained behavior, which limits their access to the blood circulation required for efficient systemic antibody-mediated cell depletion. Although LN B cells are spatially segregated from FcγR+ effector cells, remodeling of the LN microenvironment through irradiation enabled anti-CD20 mAb-mediated B cell depletion. Our findings identify LN architecture as a structural barrier to depleting antibody-based therapies and highlight tissue remodeling as a strategy to enhance therapeutic responses within lymphoid organs.