Emerging frontiers in targeted and immunotherapeutic strategies for marginal zone lymphoma

Abstract

Marginal zone lymphoma (MZL) comprises a heterogeneous group of indolent B-cell non-Hodgkin lymphomas. Most patients have favorable outcomes, but approximately 20% develop early relapse or progression within 24 months. Advances in molecular profiling have identified recurrent alterations in B-cell receptor, NF-κB, and NOTCH signaling, together with epigenetic changes and immune microenvironment abnormalities. These findings have supported the development of targeted and immune-based therapies. Among targeted agents, Bruton tyrosine kinase inhibitors have the strongest clinical evidence in relapsed or refractory MZL. BCL-2 and PI3K inhibitors, monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapies have also been evaluated across different treatment settings. This review summarizes the molecular basis of MZL and the clinical evidence for these therapies, with emphasis on efficacy, safety, patient selection, and limitations of the available data. We also discuss treatment sequencing, biomarkers, resistance, and future strategies for individualized management.