Abbreviations
Systemic lupus erythematosus
Compound chimeric antigen receptor (dual-target CAR)
Chimeric antigen receptor T cell
B-cell maturation antigen
B-cell activating factor
Bone marrow
Peripheral blood
Plasmacytoid dendritic cell
Conventional dendritic cell
T follicular helper cell
Neutrophil extracellular trap;
Definition of remission in SLE
Lupus low disease activity state
NOD scid gamma (mouse model)
Peripheral blood mononuclear cell
SLE responder index 4
SLE responder index 6
Universal CD19-targeted CAR-T cells (CRISPR-edited allogeneic product)
Universal chimeric antigen receptor T cell (allogeneic “off-the-shelf”)
Anti-double-stranded DNA antibody
Graft-versus-host disease
Systemic Lupus Erythematosus Disease Activity Index 2000
Cytokine release syndrome
Immune effector cell-associated neurotoxicity syndrome
Introduction
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by the production of diverse autoantibodies and involvement of multiple organs. Its pathogenesis is multifactorial, arising from the interplay between genetic susceptibility, including mutations in genes such as TREX1 [ [1] , [2] , [3] ], environmental triggers such as ultraviolet radiation [ 4 ], Epstein–Barr virus (EBV) infection [ 5 ], and profound immune dysregulation [ 6 ]. Among these, aberrant activation of the innate immune system represents a central event in disease initiation. During the early stages of SLE, apoptotic cells, neutrophil extracellular traps (NETs), and mitochondrial DNA released from platelets and erythrocytes serve as major sources of self-nucleic acids [ [6] , [7] , [8] ]. Defective clearance of these cellular remnants, resulting from impaired efferocytosis and complement deficiencies such as C1q and C4 deficiency, leads to their accumulation and subsequent formation of immune complexes with autoantibodies. These immune complexes are internalized by plasmacytoid dendritic cells (pDCs) through Fc receptors, where they activate Toll-like receptors (TLR7 and TLR9) and downstream MyD88 signaling, ultimately inducing robust production of type I interferons, particularly IFN-α, a hallmark of SLE pathogenesis [ 7 ]. Notably, although pDCs have traditionally been regarded as the principal source of type I interferons, recent studies have demonstrated that, within cutaneous lesions, conventional dendritic cells (cDCs) and macrophages are the predominant producers of IFN-α and IFN-β, whereas keratinocytes contribute to disease initiation through the production of IFN-κ [ 6 ].
In addition to conventional lymphocytes, increasing attention has been directed toward the contribution of innate immune cells and unconventional lymphocyte subsets. Type 2 innate lymphoid cells (ILC2s), which normally exert protective effects through cytokines such as IL-5, are significantly reduced in patients with SLE [ 9 ]. Basophils promote follicular helper T-cell (Tfh) polarization and autoreactive IgE production through the PD-L1/IL-4 axis, thereby enhancing autoantibody generation and the development of lupus nephritis [ 4 ]. Furthermore, double-negative T (DNT; CD4 − CD8 − ) cells are consistently expanded in SLE and contribute to lupus nephritis through the production of IFN-γ [ 10 ]. Persistent activation of the type I interferon pathway further amplifies adaptive immune dysregulation and sustains disease progression. Expanded Tfh cells promote the differentiation of autoreactive B cells into long-lived plasma cells and plasmablasts through IL-21 signaling, resulting in continuous production of pathogenic autoantibodies, including anti-dsDNA, anti-Sm, and anti-Ro/La antibodies. These autoantibodies form immune complexes with self-antigens that deposit within target organs such as the kidney, activate complement, recruit inflammatory cells, and ultimately drive tissue injury, including lupus nephritis [ 11 ]. Collectively, these interconnected innate and adaptive immune abnormalities establish a self-perpetuating inflammatory circuit that drives chronic autoimmunity in SLE. This mechanistic framework provides the biological rationale for CAR-based therapeutic strategies targeting B cells and type I interferon–associated immune networks to promote immune reprogramming.
Current standard treatment for SLE consists primarily of conventional immunosuppressive agents and biologic therapies. Hydroxychloroquine and glucocorticoids remain the cornerstone of treatment for virtually all patients with SLE, substantially reducing disease activity and cumulative organ damage [ 12 ]. Combination regimens incorporating cyclophosphamide, mycophenolate mofetil, azathioprine, and calcineurin inhibitors have further improved remission rates in lupus nephritis [ 12 , 13 ]. However, a systematic review including 41 studies involving 17,270 patients demonstrated that even the most permissive definition of "clinical remission on treatment" was achieved in only 15.6%–49.6% of patients, whereas rates of "clinical remission off treatment" or "complete remission off treatment" were considerably lower [ 14 ]. Moreover, prolonged immunosuppressive therapy is associated with substantial toxicities, including infections, myelosuppression, hepatotoxicity, nephrotoxicity, and impaired fertility.
The introduction of biologic therapies has expanded the therapeutic landscape of SLE. Rituximab, the first anti-CD20 monoclonal antibody widely applied in SLE, fails to effectively eliminate tissue-resident B cells and long-lived plasma cells, resulting in considerable interpatient variability in the depth and duration of peripheral B-cell depletion and frequent disease relapse following treatment discontinuation [ 13 ]. Belimumab, which neutralizes B-cell activating factor (BAFF), suppresses B-cell survival and differentiation and achieved a 52-week SRI-4 response rate of 57.6% in the BLISS-52 trial; however, its onset of action is relatively slow, and its efficacy remains limited in patients with severe organ involvement [ 13 ]. Anifrolumab targets the type I interferon receptor and blocks aberrant interferon signaling, although its phase III trial in lupus nephritis failed to meet the primary endpoint [ 13 , 15 ]. Therefore, although current therapies provide disease control for many patients, they often fail to achieve durable, treatment-free remission in those with refractory or relapsing disease. These limitations underscore the need for therapeutic strategies capable of inducing deeper and more sustained immune reprogramming, providing the fundamental rationale for the application of CAR-T therapy in SLE.
Chimeric antigen receptor T-cell (CAR-T) therapy, initially transformative in B-cell malignancies, is now emerging as a novel therapeutic paradigm for autoimmune diseases [ 16 ]. By genetically reprogramming T cells to recognize B-cell surface antigens, CAR-T therapy enables potent and selective elimination of pathogenic B-cell populations that drive SLE [ 17 ]. Since the first report of successful anti-CD19 CAR-T therapy in refractory SLE in 2021 [ 18 ], the field has rapidly evolved along two major axes: target antigen optimization and diversification of cellular platforms. Targeting strategies have expanded from pan–B-cell markers such as CD19 and CD20 to plasma cell–associated antigens including B-cell maturation antigen (BCMA), as well as dual-target approaches (e.g., BCMA/CD19), with the aim of achieving more comprehensive and durable eradication of the B-cell lineage. In parallel, cellular platforms have advanced beyond autologous αβ T cells to include allogeneic “off-the-shelf” CAR-T cells, regulatory T cells, and innate immune effectors such as natural killer and γδ T cells, thereby addressing key limitations related to manufacturing time, cost, and toxicity.
Unlike previous reviews that have primarily summarized the clinical efficacy and safety of B-cell–directed CAR therapies in SLE, the rapid expansion of CAR-based strategies—including alternative target antigens, dual-target designs, engineered cellular platforms, and emerging clinical evidence—has created a need for a broader and more comprehensive synthesis of the field. The objective of this review is to critically evaluate current preclinical and clinical evidence for CAR-based therapies in SLE, with particular emphasis on their mechanisms of action, therapeutic efficacy, durability, safety, and translational challenges. Rather than viewing CAR-T therapy solely as a B-cell depletion strategy, we highlight the emerging concept that CAR-based therapies may contribute to immune remodeling beyond direct cellular depletion, integrating evidence from B-cell compartment reconstruction, immune reconstitution, and modulation of inflammatory networks. We further compare different target antigens and cellular platforms, including conventional CAR-T cells, next-generation dual-target constructs, and alternative immune-cell platforms such as CAR-NK and CAR-γδT cells, discuss the biological rationale underlying immune reprogramming, and highlight key knowledge gaps and future research priorities. To ensure comprehensive coverage, we systematically searched PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) for publications available through March 2026, including preclinical studies, clinical trials, case reports, and relevant systematic reviews. The available evidence was synthesized according to target antigen and cellular platform, with particular attention to current limitations and future translational directions.
CAR-T targeting B-cell lineage antigens: design strategies and clinical translation
B cells are central drivers of SLE pathogenesis, serving not only as the primary source of pathogenic autoantibodies but also actively sustaining autoimmune responses through antigen presentation and cytokine-mediated immune amplification [ 19 ]. The persistence of long-lived plasma cells and memory B cells underlies disease refractoriness and relapse, making them critical barriers to durable remission [ 20 ]. CAR-T cells, through their capacity for in vivo expansion and persistence, can achieve profound depletion of B-cell populations across peripheral and tissue compartments, potentially disrupting autoreactive immune circuits that sustain disease activity [ 21 ].
In established murine models of lupus-like disease, including MRL/lpr and NZB/W F1 mice, CAR-T cells targeting CD19 or BAFF receptor family members (BAFF-R, BCMA, and TACI) achieved profound peripheral B-cell depletion, with reductions exceeding 95% and persistence of depletion for more than 6 months. These effects were associated with decreased anti-dsDNA antibody titers, reduced proteinuria, improved glomerulonephritis pathology, and prolonged survival in treated animals. Collectively, these findings provide important preclinical evidence supporting the potential of CAR-based strategies to modulate pathogenic B-cell responses and achieve sustained disease control in lupus-like disease models [ [22] , [23] , [24] ].
Beyond cytotoxic depletion, CAR-T therapy has been proposed to induce a state of immune reconstitution that may contribute to disease remission in SLE [ 21 , 25 ]. Elimination of pathogenic B-cell populations creates a transient lymphopenic “reset window,” which may facilitate re-establishment of a more diverse and less autoreactive B-cell repertoire. Changes in regulatory and effector T-cell compartments have also been reported after CAR-T therapy, although their functional significance and contribution to immune tolerance restoration remain to be fully validated in humans [ 26 , 27 ]. Mechanistically, regenerated B cells have been reported to display a more immature phenotype with reduced autoreactive signatures, while single-cell transcriptomic analyses demonstrate suppression of type I IFN signaling across monocyte and T-cell subsets, with key inflammatory genes such as ISG15 and MX1 showing decreased expression [ [28] , [29] , [30] , [31] ]. In SLE patients, dual-target BCMA-CD19 CAR-T therapy similarly suppresses RIG-I/MDA5 and interferon-driven transcriptional programs, correlating with reductions in disease activity (SLEDAI) [ 30 ]. Collectively, these findings indicate that CAR-T therapy may extend beyond B-cell depletion by reshaping immune cell composition and inflammatory pathways, providing a potential mechanistic basis for sustained remission and supporting the emerging concept of immune reprogramming in refractory SLE ( Fig. 1 ).
CD19-targeted CAR-T therapy
CD19 is expressed throughout most stages of B-cell development, from precursor B cells to mature B cells and even some plasmablasts, making it an ideal target for achieving deep B-cell depletion [ 21 ]. Early clinical trials in refractory SLE have largely focused on this target and have demonstrated remarkable efficacy. The first reported case of lentivirus-transduced autologous CD19 CAR-T therapy in refractory SLE showed successful CAR-T cell expansion after infusion and complete and sustained depletion of circulating B cells within one week, demonstrating the feasibility and potential efficacy of this approach in refractory SLE [ 18 ]. Subsequently, the first cohort study demonstrated that five patients with active refractory SLE achieved deep B-cell depletion and significant clinical improvement after infusion of autologous CD19 CAR-T cells. Notably, even though B cells reappeared at a median of 110 days, no disease relapse was observed. Newly generated B cells were predominantly naïve and non–class-switched, while memory B-cell populations, including disease-associated activated memory B cells and plasmablasts, remained markedly reduced during immune reconstitution. The reconstituted B-cell repertoire also shifted from IgG/IgA-dominant class-switched clones at baseline to an IgM/IgD-dominant naïve state. Meanwhile, pre-existing vaccine-induced antibody levels were largely preserved, suggesting that anti-CD19 CAR-T cells mediate broad-spectrum B-cell depletion by targeting the CD19 antigen (while sparing CD19 − long-lived plasma cells). The subsequent immune reconstitution process, characterized by preferential recovery of naïve B cells, reduction of memory B cells and plasmablast populations, and remodeling of the BCR repertoire, may contribute to the attenuation of autoreactive B-cell responses and sustained clinical remission. Importantly, this effect reflects the biology of B-cell depletion and subsequent immune reconstruction rather than direct recognition of autoreactive B-cell clones by CAR-T cells [ [31] , [32] , [33] , [34] , [35] , [36] ] . After CAR-T infusion, peripheral B cells are typically depleted within two weeks and gradually reconstituted within 2–6 months, accompanied by reductions in autoantibody titers, normalization of complement levels, and improvement in proteinuria. Approximately 50% of patients develop hypogammaglobulinemia. During B-cell recovery, naïve B cells account for the majority of the reconstituted B-cell compartment (>90% in reported cohorts), whereas pre-existing memory B-cell subsets and plasmablast populations are profoundly depleted.
Chinese researchers have also made important advances in allogeneic CD19 CAR-T therapy. Although pathogenic autoantibodies in SLE are mainly produced by CD19-negative long-lived plasma cells, which raised concerns regarding the applicability of CD19 CAR-T therapy, Yang et al. used CRISPR/Cas9 technology to engineer donor T cells by knocking out TRAC, HLA-A, HLA-B, CIITA, and PD-1, thereby generating universal CD19-targeted CAR-T cells (TyU19). The study showed that even in patients with pre-existing CD19 − BCMA + plasma cells, TyU19 CAR-T therapy induced rapid B-cell depletion in all refractory patients, with significant reductions in memory B cells and plasma cells, including CD19 − BCMA + subsets, during immune reconstitution [ 37 ]. These findings suggest that depletion of CD19 + precursor B cells may interrupt the upstream supply or survival niche of autoreactive plasma cells, thereby achieving deep and durable immune reset. In one patient, repeat renal biopsy at 12 months demonstrated significant histopathological improvement in lupus nephritis, including reduced cellular and mesangial proliferation, reopening of occluded capillary loops, and marked reduction in renal CD19 expression, providing histological evidence of profound B-cell depletion [ 38 ]. Similar findings have also been observed in pediatric SLE patients [ 39 ].
BCMA-targeted and BCMA/CD19 dual-target CAR-T therapy
BCMA is preferentially expressed on terminally differentiated long-lived plasma cells, with minimal expression on early B cells [ 21 ]. In SLE, BCMA expression may be increased in antibody-producing B-cell compartments, and elevated serum soluble BCMA levels correlate with disease activity, supporting its potential as both a therapeutic target and a biomarker of immune activation [ 40 ].
Clinical trials have demonstrated that BCMA-targeted CAR-T therapy induces rapid and profound B-cell depletion. Hu et al. reported complete clearance of peripheral B cells within one month after infusion, followed by reconstitution within 3–6 months, with more than 90% of regenerated B cells exhibiting a naïve phenotype [ 41 ]. This was accompanied by suppression of inflammatory signaling pathways in B cells and CD4 + effector memory T cells, including reduced JAK activation and monocyte chemotaxis, alongside enhanced antigen presentation capacity, collectively indicating a shift toward a low-inflammatory immune state [ 41 ].
However, the therapeutic scope of BCMA targeting is constrained by clonal heterogeneity. Long-lived plasma cells in the bone marrow (BM) frequently harbor BCR repertoires distinct from peripheral B cells, limiting the ability of BCMA-directed therapy alone to fully eliminate the autoreactive lineage [ 42 ]. This limitation provides a strong mechanistic rationale for dual-target strategies. BCMA/CD19 CAR-T approaches, enabled by tandem or dual CAR designs, allow simultaneous targeting of both early B cells and terminally differentiated plasma cells, thereby improving lineage-wide clearance and reducing the risk of antigen escape [ 39 ]. Notably, BCMA-directed CAR-T cells exhibit greater persistence and higher peak expansion compared with CD19-targeted counterparts [ 42 ]. In 2021, Zhang et al. first reported successful treatment of a patient with coexisting diffuse large B-cell lymphoma (DLBCL) and SLE using compound CAR-T (cCAR) targeting CD19 and BCMA, resulting in sustained B-cell depletion for up to 9 months and absence of autoantibody re-emergence following reconstitution [ 43 ]. Subsequent studies have consistently demonstrated that dual-target CAR-T therapy achieves more complete eradication of the pathogenic B-cell–plasma cell axis, induces sustained drug-free remission in refractory SLE, and effectively eliminates autoantibodies derived from long-lived plasma cells [ 42 , 44 , 45 ]. Following cCAR infusion, peripheral B cells are typically depleted within 7–10 days, with delayed reconstitution compared with CD19-targeted therapy, occurring at a median of approximately 6 months and extending up to 1 year in some cases [ 42 , 44 , 46 ]. This prolonged depletion is associated with effective elimination of CD19 + BCMA + B-cell/plasma-cell populations associated with autoantibody production in both peripheral blood (PB) and BM. Upon reconstitution, the immunoglobulin repertoire shifts from IgG/IgA-dominant to naïve IgM/IgD-dominant profiles, indicating normalization of the B-cell compartment [ 42 , 44 , 46 ]. Concurrently, interferon-stimulated gene signatures and BAFF-dependent pathways are persistently suppressed, suggesting a shift toward a less inflammatory immune state [ 42 ].
Although early reductions in immunoglobulin levels are more pronounced than with CD19-targeted therapy (approximately 80–90%), mucosal immunity and vaccine-induced antibody responses are ultimately restored, indicating functional reprogramming rather than irreversible impairment of humoral immunity [ 42 , 44 , 46 ]. Importantly, Hong et al. performed repeat renal biopsies in 9 out of 10 lupus nephritis patients approximately one year after cCAR-T therapy, demonstrating marked histopathological improvement, including resolution of cellular crescents, reduction in mesangial and endothelial proliferation, attenuation of glomerular basement membrane “spike” formation, and complete clearance of immune complex deposition [ 46 ]. These findings confirm that serological remission translates into tissue-level resolution of immune pathology. Notably, persistent proteinuria in individual cases despite serological remission reflects irreversible chronic damage rather than ongoing immune activity, underscoring the importance of distinguishing active disease from established organ injury. Collectively, these findings demonstrate that dual-target CAR-T therapy may provide broader depletion across B-cell lineage compartments compared with single-antigen approaches, marking a transition from broad B-cell depletion toward integrated depth and breadth of immune clearance in refractory SLE.
CD20 and CD22-Targeted CAR-T therapy
Beyond CD19 and BCMA, alternative targets have been explored to optimize CAR-T therapy for SLE and to address antigen escape or improve B-cell depletion. CD20 and CD22, as pan–B-cell markers, represent potential targets. CD20-directed approaches are inherently limited by the absence of CD20 expression on plasma cells, and large clinical trials of rituximab have failed to demonstrate superiority over placebo in SLE, underscoring the insufficiency of CD20 targeting alone to eliminate pathogenic B-cell subsets [ 47 ]. CD22, characterized by rapid internalization, offers a mechanistic advantage for CAR-T targeting and has shown therapeutic activity in preclinical SLE models [ 48 ]. Nevertheless, single-target approaches against CD20 or CD22 are unlikely to fully abrogate the autoreactive B-cell–plasma cell axis, particularly in eliminating early B-cell populations and long-lived plasma cells responsible for sustained autoantibody production, thereby limiting their efficacy compared with CD19 − or BCMA-directed strategies [ 49 ].
These limitations provide a rationale for combinatorial targeting. Mao et al. reported the first successful application of bicistronic CD19/CD22 CAR-T therapy in three pediatric patients with refractory lupus nephritis [ 50 ]. Using a lentiviral construct encoding both CD19 − and CD22-targeting CARs under a single promoter via a self-cleaving 2A peptide, this dual-target design enables a coordinated “double-hit” mechanism. CD19 targeting mediates broad depletion of the B-cell lineage, including CD20-negative plasmablasts and plasma cells resistant to anti-CD20 therapy, while CD22 targeting enhances cytotoxicity and suppresses B-cell receptor signaling, thereby more effectively resetting aberrant B-cell immunity. Building on prior success in B-ALL, this dual-target strategy is designed to overcome antigen escape and achieve deeper and more durable depletion of pathogenic clones. Clinically, all patients achieved marked remission within 3 months after infusion and maintained drug-free remission during 9–15 months of follow-up, accompanied by profound B-cell depletion and reconstitution dominated by naïve B cells [ 50 ]. Collectively, these findings suggest that multi-target CAR-T strategies may overcome the limitations of single-antigen targeting and provide a more robust approach to achieving durable immune reprogramming in refractory SLE.
Summary of B-cell reconstitution and immune reprogramming
Accumulating evidence suggests that the long-term therapeutic benefit of CAR-T therapy in SLE extends beyond transient B-cell depletion and may be closely associated with the subsequent pattern of B-cell reconstitution ( Fig. 2 ). Across studies of CD19 − , BCMA-, and dual-target CAR-T therapies, profound depletion of peripheral B cells is consistently followed by an orderly recovery process. B cells re-emerge from bone marrow precursors and are initially dominated by transitional and naïve B-cell subsets, whereas class-switched memory B cells, activated autoreactive B cells, and plasmablasts recover substantially later. This characteristic pattern of reconstitution has therefore been proposed as a functional B-cell immune reprogramming, distinguishing CAR-T therapy from conventional B-cell–depleting strategies.
Mechanistically, this process may result from elimination of the pre-existing autoreactive B-cell repertoire together with interruption of pathogenic interactions between B cells, Tfh cells, plasmablasts, immune complexes, and type I interferon–driven inflammatory circuits. Concurrently, regenerated B cells exhibit a predominantly naïve phenotype with an IgM/IgD-enriched B-cell receptor repertoire, accompanied by attenuation of interferon-associated transcriptional programs and BAFF-dependent signaling. These coordinated changes suggest that CAR-T therapy may reshape both the composition of the B-cell compartment and the broader immune microenvironment, providing a plausible biological basis for sustained drug-free remission.
Nevertheless, the concept of immune reprogramming should be interpreted cautiously. Current evidence is largely derived from small, uncontrolled clinical studies, and definitive restoration of antigen-specific immune tolerance has not yet been demonstrated. Furthermore, long-lived plasma cells lacking CD19 expression may escape direct depletion, providing the rationale for BCMA-directed or dual CD19/BCMA-targeted strategies that extend immune clearance across the B-cell lineage. Whether these approaches translate into more durable immune reprogramming and superior long-term clinical outcomes remains to be confirmed in larger prospective studies with comprehensive mechanistic analyses.
CAR-T targeting Non–B-Cell lineages
CAR-NK and CAR-γδ T cells
Non–B-cell–directed strategies represent an emerging direction in CAR-based therapy for SLE, aiming to modulate disease through alternative immune pathways. Among these, CAR-engineered innate immune effectors, particularly NK cells and γδ T cells, offer distinct advantages over conventional CAR-T approaches by enabling MHC-independent target recognition and minimizing the risk of graft-versus-host disease (GVHD), thereby making them ideal “off-the-shelf” cellular sources.
CAR-NK therapy has emerged as a promising alternative with a favorable safety profile and broader accessibility [ 51 , 52 ]. Fu et al. engineered CD19-targeted CAR-NK cells (XB-19.15) incorporating a secretable IL-15 module to overcome limited in vivo persistence. In humanized SLE PBMC mouse models, this approach significantly reduced total IgG and anti-dsDNA antibody levels and effectively eliminated B cells, plasmablasts, and plasma cells in BM and spleen. In an early phase I study of three patients with refractory SLE, B-cell depletion was achieved by week 4, with reconstitution beginning at week 12, while serum IgG and complement C3 levels remained stable, indicating preservation of humoral immune homeostasis [ 53 ]. Similarly, Gao et al. developed CD19-targeted CAR-NK cells incorporating 4-1BB and CD3ζ signaling domains along with membrane-bound IL-15 to enhance persistence. These cells demonstrated potent cytotoxicity against malignant CD19 + B-cell lines (NALM-6, Raji) and primary B cells from SLE patients, with in vivo efficacy validated in xenograft NSG mouse models. Clinically, despite shorter persistence compared with CAR-T cells, CAR-NK therapy achieved deep and sustained B-cell depletion, with 89% of patients reaching profound depletion (CD19 + <5 cells/μL). Upon reconstitution, the B-cell compartment was predominantly naïve (up to 96%), with marked reductions in pre-existing memory B-cell populations, including CD11c + activated memory B cells, as well as plasmablasts. Notably, 71% of patients exhibited reversal of immunoglobulin class switching, with dominant isotypes shifting from IgG/IgA to IgD/IgM, alongside contraction of dominant clones and restoration of polyclonal diversity. Serum IgG levels remained stable in all patients without the need for immunoglobulin replacement [ 54 ]. These findings suggest that CAR-NK therapy may induce remodeling of dysregulated B-cell compartments and provide a favorable safety profile due to lower cytokine release and faster immune recovery.
In contrast, CAR-γδ T-cell approaches remain at an early stage of development. Engineered γδ T cells targeting CD19 or BCMA can directly eliminate autoreactive B cells through perforin–granzyme and death receptor pathways, while also modulating immune responses via cytokine secretion and interaction with dendritic cells and regulatory T cells, thereby potentially restoring immune tolerance [ 55 ]. However, translational challenges remain substantial. In preclinical models, CD19-targeted CAR-γδ T cells induced a 65% reduction in anti-dsDNA antibody levels and a 40% improvement in proteinuria at week 4, but these effects were not sustained, with disease parameters rebounding by week 8 [ 56 ]. Clinical data further highlight limitations in persistence. In a phase I trial for relapsed/refractory multiple myeloma, allogeneic CAR-γδ T cells exhibited a median persistence of only 14 days in PB [ 57 ], and in solid tumor studies, fewer than 30% of patients retained detectable CAR-γδ T cells at day 28 [ 58 ]. These findings identify insufficient in vivo expansion and persistence as key bottlenecks for CAR-γδ T-cell therapy. In the context of SLE, where long-term immune regulation is required, these limitations represent a major barrier to clinical translation.
CAR-Treg therapy
CAR-Treg therapy represents a fundamentally distinct, non-depletive approach in contrast to conventional cytotoxic CAR-T strategies. Rather than eliminating B cells, CAR-Tregs are engineered to redirect the immunosuppressive function of regulatory T cells toward antigen-specific microenvironments enriched for disease-associated B-cell populations or plasma cells, such as those expressing CD19 or BCMA. This approach aims to locally suppress autoreactive immune responses and restore tolerance while potentially preserving physiological B-cell function [ 59 ].
In the context of SLE, CAR-Tregs exert their effects through multiple complementary mechanisms, including direct suppression of autoreactive T- and B-cell activation, induction of tolerogenic dendritic cells, and reprogramming of the inflammatory cytokine milieu from a pro-inflammatory state (e.g., IFN-γ, IL-17) toward a regulatory profile (e.g., IL-10, TGF-β), thereby promoting restoration of immune homeostasis [ 60 ]. Doglio et al. engineered CD19-targeted CAR-Tregs (Fox19CAR-Tregs) via lentiviral transduction combined with overexpression of the key transcription factor FoxP3. In two humanized SLE mouse models, adoptive transfer of these cells significantly attenuated disease-associated B-cell dysregulation, reduced anti-dsDNA autoantibody levels, and alleviated inflammatory tissue damage in the spleen, lungs, and kidneys, ultimately restoring immune balance. Notably, this approach demonstrated a favorable safety profile, avoiding B-cell aplasia observed with conventional CAR-T cells while producing anti-inflammatory cytokines such as IL-10 without inducing cytokine release syndrome (CRS) [ 61 ]. Although still in early development, CAR-Treg therapy represents a distinct strategy that interrupts autoimmunity by shifting from cell depletion to antigen-specific immune regulation, with the potential to restore durable immune tolerance in SLE.
CAR-T platforms in SLE: autologous, allogeneic, and in vivo approaches
CAR-T therapy for SLE is currently being developed along three principal platforms: autologous, allogeneic (“off-the-shelf”), and in vivo–generated CAR-T approaches, each with distinct advantages and limitations. Autologous CAR-T therapy, derived from patient T cells, minimizes the risk of immune rejection but is constrained by prolonged manufacturing time, high cost, and variability in T-cell fitness. In SLE, disease-related immune dysregulation and prior immunosuppressive therapy may impair T-cell function, potentially compromising the efficacy and persistence of the final product [ 31 , 62 ]. Allogeneic CAR-T (UCAR-T), generated from healthy donors and optimized through gene editing, enables rapid availability and standardized production. By disrupting endogenous T-cell receptors and HLA expression, UCAR-T reduces the risks of GVHD and host rejection [ 63 ]. However, incomplete immune evasion and residual antigenicity may still lead to host-mediated clearance, limiting long-term persistence and therapeutic durability [ 64 ].
In vivo–generated CAR-T therapy represents a paradigm shift by bypassing ex vivo manufacturing altogether. Using viral or non-viral delivery systems, CAR constructs are directly introduced into patient T cells, enabling rapid in situ reprogramming. In a first-in-human clinical trial, Wang et al. delivered CD19 CAR mRNA via CD8-targeted lipid nanoparticles in five patients with refractory SLE, achieving detectable CAR-T cells within 6 h and rapid B-cell clearance. Four patients developed grade 1 CRS and one developed grade 2, with no cases of ICANS. At 3 months, median SLEDAI decreased from 8.5 to 6; autoantibodies became negative in one patient, complement levels normalized in three, and proteinuria decreased in all three affected patients [ 65 ]. These findings may offer advantages in manufacturing simplicity and accessibility of in vivo CAR-T generation, while offering key advantages in speed, scalability, and cost by eliminating complex manufacturing and lymphodepletion steps. However, several challenges remain, including achieving cell-specific delivery to avoid off-target transduction, improving transduction efficiency to ensure sufficient CAR-T generation, and precisely controlling in vivo activation, expansion, persistence, and clearance to minimize long-term toxicity. Furthermore, the durability of response and the potential to achieve sustained treatment-free remission require validation in larger cohorts and longer follow-up [ 66 ].
Clinical efficacy and safety profiles of CAR-based therapies in SLE
Clinical efficacy and durability
Clinical studies have provided encouraging evidence supporting the potential efficacy and feasibility of CAR-based therapies in refractory SLE ( Table 1 ), with completed and ongoing/planned studies summarized in Supplementary Tables S1 and S2 , respectively.
In a systematic review by Sayed et al., which included 47 patients across 10 clinical trials primarily employing CD19-targeted and dual-target BCMA-CD19 CAR-T therapies, 81% of patients achieved lupus low disease activity state (LLDAS), while the median SLEDAI-2K score decreased from 12 at baseline to 0 at last follow-up. These responses were accompanied by profound B-cell depletion, marked reductions or seroconversion of anti-dsDNA antibodies, normalization of complement levels, and resolution of proteinuria, enabling treatment-free remission in the majority of patients [ 72 ]. Similarly, Nordmann et al. summarized 16 clinical trials involving 145 patients treated with CD19-directed or dual-target CD19/BCMA CAR-T therapies and reported a substantial reduction in disease activity, with mean SLEDAI decreasing from 13.1 at baseline to 2.3 at 6 months and further to 1.4 at 12 months. Clinical remission according to DORIS criteria was achieved in 70% (45/64) of patients, while 89% (50/56) reached LLDAS, and more than 80% discontinued immunosuppressive therapy [ 73 ]. Importantly, these responses extended across severe disease phenotypes, including lupus nephritis [ 41 , 67 ], refractory thrombocytopenia [ 68 , 74 ], and central nervous system involvement [ 69 ], highlighting the broad clinical applicability of B-cell–directed CAR-T strategies in otherwise treatment-refractory settings.
Emerging clinical trial data further support the efficacy of alternative CAR platforms. In an early clinical trial conducted by Fu et al., all three patients receiving allogeneic CD19-targeted CAR-NK therapy achieved SRI-4 responses within 6 months, with median SLEDAI-2000 decreasing from 10.5 to 4, and two patients successfully discontinued therapy [ 53 ]. In a larger cohort reported by Gao et al., 17/17 (100%) evaluable patients treated with CD19 CAR-NK cells achieved SRI-4 responses at 6 months, with 94% achieving SRI-6 responses. Additionally, 72% achieved DORIS remission and 78% reached LLDAS, with durable responses observed at 12 months, where SRI-6 response rates reached 100%. Rapid clinical improvement was evident, with 14 patients achieving SLEDAI-2K scores below 4 within 3 months, and 80% of patients with proteinuria achieving complete resolution within the same period [ 54 ].
In contrast, in vivo–generated CAR-T approaches remain in early clinical development. In a first-in-human clinical trial by Wang et al., CD19-targeted CAR-T cells generated in vivo via lipid nanoparticle delivery demonstrated rapid B-cell depletion and preliminary clinical efficacy, although long-term durability and optimal dosing strategies remain to be established [ 65 ]. Collectively, these data indicate that B-cell–directed CAR-T therapies, particularly autologous CD19-targeted and dual-target BCMA/CD19 approaches, induce rapid, deep, and durable remission in refractory SLE, while alternative platforms such as CAR-NK and in vivo CAR-T provide promising complementary strategies with distinct translational advantages.
Safety profile and adverse event management
Compared with lymphoma patients, CAR-based therapies in SLE are associated with a lower incidence and severity of CRS and ICANS, likely reflecting differences in baseline immune activation and disease biology [ 72 , 73 , 75 ]. Across clinical trials primarily involving autologous CD19-targeted and dual-target BCMA/CD19 CAR-T therapies, CRS represents the most common adverse event but is generally mild and manageable. In the cohort summarized by Sayed et al., 41 of 47 patients developed CRS, all of which (100%) were grade 1–2 and resolved with supportive care or treatment with glucocorticoids and tocilizumab. Only one case of mild ICANS was reported, which resolved with steroid therapy. Other adverse events, including infections and transient cytopenias, were self-limited, and no patients required intensive care [ 72 ]. Similarly, in the larger analysis by Nordmann et al., CRS occurred in 55.9% of patients, with 98.8% classified as grade 1–2 and only one grade 3 event. ICANS occurred in 2.8% of patients and was reversible in all cases. Additional adverse events included severe infections (7.6%), grade 3–4 hematologic toxicity (40%), and hypogammaglobulinemia, with one treatment-related death attributed to pneumococcal meningitis [ 73 ]. These findings indicate that, although immune-mediated toxicities remain common, their severity is substantially attenuated in SLE compared with oncologic settings.
Safety profiles vary across CAR platforms. In clinical trials of allogeneic CD19 CAR-NK therapy, toxicity was notably reduced, with only one case of grade 1 CRS reported among 21 patients and no cases of ICANS or hypogammaglobulinemia, highlighting the favorable safety profile of innate immune–based approaches [ 53 , 54 ]. Special populations further illustrate both the safety and complexity of CAR-based therapies. A reported case of successful pregnancy following CAR-T therapy in a patient with severe refractory SLE suggests preservation of immune competence and potential long-term safety [ 76 ]. This case highlights the potential of CAR-T therapy as a curative strategy for refractory, highly active SLE, particularly in young patients with reproductive considerations.
In pediatric SLE, early clinical experience indicates that low-dose CD19 CAR-T therapy (1 × 10 5 cells/kg) can achieve sustained B-cell depletion with only grade 1 CRS and mild neurotoxicity, both fully reversible [ 70 ]. Similarly, Becilli et al. reported that higher-dose therapy (1 × 10 6 cells/kg) was well tolerated in four pediatric SLE patients, all of whom developed only grade 1 CRS. Notably, three patients achieved DORIS-defined complete remission within 6 months, accompanied by marked improvement or normalization of lupus nephritis–associated proteinuria, hypocomplementemia, and anti-dsDNA antibody levels [ 39 ]. These findings further support the capacity of CD19-directed CAR-T therapy to induce deep and durable responses in pediatric SLE, suggesting the potential to achieve clinical cure–like outcomes. However, severe toxicity may occur in high-risk settings. A pediatric patient receiving dual-target CD19/CD22 CAR-T therapy developed grade 4 CRS complicated by hemophagocytic lymphohistiocytosis and thrombotic microangiopathy, requiring intensive care but ultimately achieving drug-free remission at 6 months [ 50 ]. This case underscores the importance of careful patient selection and pre-treatment disease control in patients with high disease activity or systemic involvement. Beyond these early experiences, CAR-T therapy is entering clinical evaluation in pediatric-onset SLE. The FDA has authorized a clinical trial of CAR-T cells in cSLE, highlighting the emerging potential of immune-resetting approaches for children with severe refractory disease. Further studies are required to establish long-term efficacy, safety, and patient selection criteria [ 77 ].
Beyond acute toxicity, long-term safety considerations remain critical. Profound B-cell depletion may transiently impair humoral immunity, necessitating immunoglobulin replacement and infection prophylaxis [ 21 ]. Secondary malignancy remains a theoretical concern related to viral vector integration, although no cases have been reported in SLE to date, warranting long-term surveillance [ 75 ]. An additional clinical challenge is disease flare during the immunosuppressive washout period prior to CAR-T therapy. Gerber et al. reported a severe lupus flare characterized by fever, rash, arthritis, elevated anti-dsDNA antibodies, and hypocomplementemia, which was successfully controlled with short-term high-dose intravenous methylprednisolone (initial 250 mg, tapered to 10 mg/day within 5 days). Importantly, this intervention did not impair CAR-T expansion or therapeutic efficacy, supporting the feasibility of corticosteroid “bridging” strategies in this setting [ 35 , 37 , 71 ].
Challenges and future directions
CAR-based therapies represent a promising approach for refractory SLE by enabling deep immune resetting through targeted modulation of pathogenic immune compartments. However, current evidence remains preliminary, with available data largely derived from small, single-center, non-randomized studies with limited follow-up duration. Although durable treatment-free remission has been reported, the long-term sustainability of immune reconstitution, disease control, and potential late safety concerns require further validation. Large-scale multicenter studies and randomized controlled trials are warranted to define the long-term efficacy, safety, and optimal clinical positioning of CAR-based therapies in SLE.
Beyond biological optimization, further advancement of adoptive cellular therapies will require improvements in manufacturing strategies, product accessibility, and scalability. Current CAR therapies rely largely on individualized manufacturing processes requiring specialized facilities and substantial healthcare resources, which limit scalability and global accessibility. Emerging strategies, including allogeneic CAR products and in vivo CAR-T generation, may overcome some of these limitations by reducing manufacturing complexity and improving availability.
Conclusion
CAR T-cell therapy is emerging as a promising approach that may reshape the treatment paradigm of refractory SLE, shifting from broad immunosuppression to targeted immune reset. Accumulating clinical evidence demonstrates that CD19 − and BCMA-directed strategies can induce rapid, deep, and durable remission, even in highly refractory disease. Beyond B-cell depletion, CAR-T therapy reshapes the immune repertoire and may promote immune reconstitution and restoration of immune balance, providing a potential basis for sustained treatment-free remission.
Key challenges remain, including optimizing patient selection, defining the therapeutic window, and mitigating long-term effects of B-cell depletion. With advances in CAR design and biomarker-guided strategies, CAR-T therapy has the potential to transform the management of autoimmune disease toward durable immune restoration.
CRediT authorship contribution statement
Wei Zhao: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Man Chen: Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Jing Long: Writing – original draft, Writing – review & editing. Peihua Lu: Writing – review & editing. Jingyu Jin: Writing – review & editing.
Ethics approval and consent to participate
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Hebei Yanda Lu Daopei Hospital.
Consent for publication
not applicable.
Funding
This study received no external funding.
Declaration of competing interests
The authors declare no conflict of interest.
Acknowledgement
not applicable.
Footnotes
Supplementary data related to this article can be found online at https://doi.org/10.1016/j.jtauto.2026.100394 .
Contributor Information
Jing Long, Email: 18813159356@163.com.
Jingyu Jin, Email: 13683517872@163.com.
Supplementary data
The following are the Supplementary data related to this article:
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Data availability
Data will be made available on request.
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Associated Data
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Data Availability Statement
Data will be made available on request.