Molecular Mechanisms of Resistance to Bispecific Antibodies in Diffuse Large B-Cell Lymphoma

CD20 × CD3 bispecific antibodies (BsAbs) have emerged as a meaningful therapeutic option for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), redirecting endogenous T cells against malignant B cells independently of major histocompatibility complex-mediated antigen presentation, and have received regulatory approval after at least two prior lines of therapy. However, a substantial proportion of patients experience primary resistance or early relapse, underscoring the need to characterize the underlying biological mechanisms, which are the focus of this review. Several tumor-intrinsic determinants of resistance have been identified, including CD20 loss driven by MS4A1 mutations, alternative splicing, and gene deletion, as well as genomic reprogramming involving TP53, MYC, and NOTCH1 alterations. T-cell dysfunction represents another critical resistance domain, encompassing inadequate intratumoral cytotoxic CD8+ T-cell infiltration, expansion of immunosuppressive regulatory and follicular helper T cells, progressive exhaustion with upregulation of PD-1, LAG-3, TIM-3, and TIGIT, and impaired T-cell fitness from prior treatment exposure. Microenvironmental barriers, including checkpoint ligand upregulation, PD-L1-enriched extracellular vesicles, spatial exclusion of effector cells from immune-cold germinal center-like niches, hypoxia, and metabolic competition, further reinforce immune escape. Emerging strategies to overcome resistance include epigenetic priming, checkpoint inhibitor combinations, 4-1BB costimulatory approaches, and next-generation multispecific antibody designs.