Mechanism-based strategies including CAR-T and bispecific engagers offer options for rituximab-resistant primary membranous nephropathyNew Strategies Target Treatment Resistance in Membranous Nephropathy

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.