Precision immunotherapies for systemic lupus erythematosus: From pathogenic targets to translational horizons

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder in which aberrant B-cell activation, persistent autoantibody production, and dysregulated cytokine and intracellular signaling networks converge to produce relapsing-remitting, multisystem inflammation and cumulative organ damage. Although conventional immunosuppressants remain the backbone of care and can attenuate disease activity, their insufficient specificity, dose-dependent toxicities, and inability to re-establish durable immunologic tolerance limit long-term disease control. Converging advances in human immunology, molecular medicine, and cell engineering are now enabling a paradigm shift toward mechanism-based precision therapies. In this review, we synthesize three interconnected therapeutic domains that collectively architect this transition: (i) selective targeting of immune-cell surface antigens and costimulatory pathways-for example, BAFF/APRIL antagonism and CD19-directed CAR-T strategies that deplete or recalibrate autoreactive B-cell compartments; (ii) modulation of proinflammatory cytokine networks and intracellular signaling cascades-including IFN-I pathway blockade and pharmacologic inhibition of JAK/STAT and mTOR axes-to dampen upstream drivers and nodal amplifiers of lupus immunopathology; and (iii) next-generation, autoantibody-focused approaches-such as mimetic peptides, CAAR-T cells, and antigen-specific Tregs-that aim to confine immune intervention to pathogenic antigenic circuits while minimizing systemic immunosuppression. We further construct a comprehensive clinical implementation roadmap to evaluate the realistic scalability, accessibility, and translational windows of these therapies over the next 5 to 10 years. Crucially, we highlight the emerging role of artificial intelligence (AI) and machine learning in addressing inter-patient heterogeneity-ranging from multi-omic molecular endotyping and predictive therapeutic modeling to the computational design of next-generation antibodies and CARs. Synergizing these mechanistic and strategic breakthroughs may accelerate progress toward mechanism-guided, individualized, and durable disease control and remission in SLE.