Targeted therapies and resistance mechanisms in lymphoma: Current landscape and emerging solutions

Lymphomas represent a diverse group of hematologic malignancies with variable clinical behavior and underlying biology. The fifth edition of the WHO classification (WHO-HAEM5, 2022) provides an updated, lineage-based framework to categorize lymphoid neoplasms, integrating immunophenotypic, genetic, and clinical features. With advancements in molecular profiling and immunotherapy, targeted treatments have transformed the therapeutic landscape of both Hodgkin and non-Hodgkin lymphomas. This review delineates the critical role of cell surface and intracellular receptors-including CD19, CD20, CD30, PD-1, and CCR4-in lymphoma pathogenesis and as therapeutic targets. We comprehensively evaluate FDA-approved targeted agents, including monoclonal antibodies (rituximab, brentuximab vedotin, obinutuzumab, mogamulizumab), immune checkpoint inhibitors (nivolumab, pembrolizumab), CAR T-cell therapies (axi-cel, tisa-cel, liso-cel, brexu-cel), bispecific T-cell engagers (mosunetuzumab, epcoritamab), and small-molecule inhibitors (ibrutinib, idelalisib, venetoclax). Each class is appraised for mechanism of action, efficacy, and safety in key lymphoma subtypes. Despite significant progress, therapeutic resistance remains a major obstacle. We categorize resistance mechanisms as antigen loss or modulation, pathway reactivation, immune microenvironment adaptation, and genetic/epigenetic evolution. Examples include CD19 antigen loss post-CAR-T therapy, BTK mutations conferring ibrutinib resistance, and immune checkpoint upregulation impairing T-cell function. Emerging strategies to counteract resistance include rational combination therapies, dual-targeted CAR constructs, next-generation bispecific antibodies, and precision-guided immunotherapy. Integration of biomarker profiling, real-time resistance monitoring, and novel immune-engineering approaches offers potential to overcome current therapeutic limitations. In conclusion, understanding the molecular basis of lymphoma and resistance mechanisms is critical to optimizing targeted therapy. This review synthesizes current evidence to inform clinical decision-making and outlines future directions for durable, personalized lymphoma care.