Treatment strategies for rituximab-resistant primary membranous nephropathy: from resistance mechanisms to emerging therapies.

With the expanding identification of target antigens in primary membranous nephropathy (PMN), treatment is shifting from empirical immunosuppression toward mechanism-based precision immunotherapy. Although rituximab (RTX) has substantially improved the management of PMN, a considerable proportion of patients still experience suboptimal response, relapse, or resistance. Accumulating evidence indicates that RTX resistance is a multifactorial process involving anti-drug antibody formation, reduced bioavailability, incomplete depletion of pathogenic B cells within lymphoid compartments, CD20 internalization and degradation, epitope spreading, persistence of autoantibodies against intracellular antigens, and genetic susceptibility. In response, a broad range of mechanism-guided therapeutic strategies is emerging, including next-generation anti-CD20 monoclonal antibodies, agents targeting distinct stages of B-cell differentiation, and advanced immune-engineering approaches such as CAR-T, CAAR-T, CAAR-NK, CAR-Treg, CAR-macrophage therapies, sweeping antibodies, antibody-drug conjugates, and bispecific autoantigen-T-cell engagers. In parallel, interventions targeting aberrant T-B cell crosstalk and complement activation are providing additional therapeutic opportunities for refractory disease. This review systematically summarizes the major pathogenic mechanisms underlying RTX-resistant PMN and integrates the latest advances in mechanism-based therapeutic strategies, with the aim of informing individualized treatment approaches and future translational research for refractory PMN.