Introduction: the scope and focus of the review
Lupus nephritis (LN), one of the most common and severe complications of systemic lupus erythematosus (SLE), affects approximately 50% of SLE patients within the first 1.5 years of SLE diagnosis [ 1 ]. It disproportionately affects women than men, and black (30–50%), Hispanic (30–40%) and Asian (30–55%) individuals compared to white (14–23%). The disease etiology involves a complex interaction of genetic factors and environmental triggers. Genome-wide association studies have identified several susceptibility loci, including those affecting complement proteins, interferon (IFN) signaling pathways, and HLA class II alleles, which contribute to immune dysregulation [ 2 – 4 ]. Environmental triggers, such as infections or UV radiation, induce cellular damage which leads to release of intracellular self-antigens like dsDNA, RNA and histones, causing formation of self-reactive antibodies (autoantibodies) and break in immune tolerance [ 5 ].
The clinical course of LN often involves cycles of active disease (flare-ups) and periods of remission. Over time, episodes of flare-ups can lead to cumulative kidney damage and progression to end-stage renal disease (ESRD). Recent epidemiological studies indicate that approximately 13% of LN patients progress to ESRD within the first 10 years of diagnosis, requiring kidney transplantation [ 6 ]. The 10-year survival rate post-LN diagnosis is around 61%, with infection being the leading cause of mortality [ 6 ]. Thus, development of effective and targeted therapeutic strategies is crucial to improve patient outcomes.
The standard of care (SOC) involves high-dose corticosteroids combined with either mycophenolate mofetil (MMF) or cyclophosphamide for induction therapy. Despite their widespread use as SOC, MMF and cyclophosphamide are used off-label, and corticosteroids represent the only FDA-approved induction therapy. Induction period typically lasts 3–6 months, followed by combination maintenance therapy with MMF or azathioprine for at least 36 months [ 7 ]. Still, these treatments are associated with high relapse rates, long-term toxicity and variable patient responses. Therapeutic innovation in LN has been particularly challenging, with little change over the past five decades.
One reason for this lag is the complexity of clinical trial design, which has been hindered by the lack of validated biomarkers and well-defined clinical endpoints. Biomarker discovery has become a critical focus in LN, particularly for monitoring disease activity, therapeutic responses, and improving patient stratification. While anti-dsDNA antibodies and complement levels are widely used clinical biomarkers, they have limitations in predicting disease activity at a molecular level before clinical symptoms arise. Identifying predictive biomarkers that signal impending flare-ups could enable earlier intervention and more personalized treatment strategies. By integrating such molecular biomarkers into diagnostic and therapeutic frameworks, patients and clinicians may be able to mitigate disease exacerbations and improve long-term outcomes for LN patients.
Another reason contributing to the slow pace of therapeutic innovation in LN is the overwhelming complexity of its immune landscape, which involves both innate and adaptive immune responses and more than 20 distinct immune cell subtypes located within kidneys [ 8 ]. Therapeutic innovation focused on targeting single antigens, despite the disease’s complexity involving genetic, environmental, clinical and immune factors, resembling cancer in its intricacy. Additionally, targeted therapies have aimed at symptom management through suppression or depletion of lymphocytes and plasma cells, and neutralization of inflammatory mediators. Future therapeutic innovation will have to shift toward mechanistically driven treatment strategies. Cell therapy like chimeric antigen receptor (CAR)-T cells directed against B-cell antigens, have emerged as promising interventions for LN, and represent a shift toward personalized strategies and possibly improved long-term outcomes in LN.
This review, approached from the standpoint of immune system dysregulation, examines how recent advances in immunopathology and targeted therapies are reshaping the treatment landscape in LN, and highlights future perspectives for integrating these innovations into more precise and adaptive care strategies.
Overview of the immunopathogenesis
The pathogenesis of SLE and LN involves both innate and adaptive immune responses, autoantibody production, complement activation and secretion of inflammatory mediators, all of which contribute to chronic inflammation and subsequent tissue injury in the kidney. The innate immune system plays a critical role in initiating as well as propagating LN. Environmental triggers induce cellular damage and death, and activate neutrophils to release neutrophil extracellular traps (NETs) in SLE and LN [ 9 ]. NETs, being composed of DNA and histones, activate plasmacytoid dendritic cells (pDCs) and myeloid DCs (mDCs) through IFN-α production and upregulation of Toll-like receptors (TLRs) TLR7 and TLR9, which recognize self-RNA and self-DNA. Macrophages polarize into pro-inflammatory M1 subtype and infiltrate the glomeruli and tubulointerstitial areas, releasing reactive oxygen species (ROS) and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and IL-1β and, all of which exacerbate inflammation and tissue damage. Anti-inflammatory M2 macrophages in an attempt to resolve inflammation, can drive renal fibrosis by consistent production of transforming growth factor-beta (TGF-β) [ 10 ]. In response to IFN stimulating genes and self-antigens, myeloid DCs become activated and stimulate adaptive immune responses, which leads to the break in immune tolerance and production of autoantibodies [ 5 ]. T cell-dependent activation of B cells is evident by class-switching and somatic hypermutation observed in autoantibodies.
Immune cell composition and key signaling networks in LN
Lupus nephritis (LN) is characterized by immune complex (IC) deposition in the kidneys. This event leads to activation macrophages and complement, and the recruitment of immune cells that exacerbate inflammation and produce local autoantibodies (Fig. 1 ). Studies employing high-resolution single-cell RNA sequencing (scRNAseq) of LN kidneys have shed light on a complex landscape of myeloid and lymphoid cell populations, each contributing to distinct aspects of LN pathogenesis.
Fig. 1 Immunopathogenesis in LN. Created in BioRender. Braunstein, M. (2025) https://BioRender.com/blhex3n
Myeloid compartment
Lineage-tracing studies revealed specialized functions and distinct phenotypes of macrophages in LN kidneys. Broadly, macrophages are categorized into tissue-resident macrophages (TrMacs) and monocyte-derived macrophages (MoMacs). As demonstrated in a mouse model, tissue-resident macrophages (F4/80 hi ) are derived from embryonic stem cells [ 11 ] and have limited ability for an IC uptake. Instead, they contribute to kidney inflammation through secretion of chemotactic factors and recruitment of proinflammatory cells into the renal parenchyma. They also secrete BAFF, which supports formation of tertiary lymphoid follicles and local B cell differentiation [ 8 , 12 ]. In addition to their role in inflammation, they also contribute to inflammatory resolution by expressing anti-inflammatory mediators while downregulating proinflammatory genes.
Bone marrow-derived monocytes/macrophages (F4/80 low ) on the other hand, are highly phagocytic, have high Fcγ receptor (FcγR) expression and are capable of efficiently internalizing and presenting IC-associated antigens [ 12 ]. They contribute to both inflammation and immune resolution in LN. Among the earliest immune cells to enter the kidney are patrolling monocytes that are characterized by the expression of CX3CR1 and CD16. Upon exposure to the local proinflammatory cytokine milieu (IFNγ, TNFα, GM-CSF), monocyte undergo differentiation into proinflammatory M1 subtype. M1 cells secrete IL-1β, TNFα and IL-6, thereby exacerbating inflammation. Over the course of immune resolution, M1 cells transition to a more reparative M2 subtype. However, as reflected in single-cell transcriptomic data on patient LN kidney samples this binary classification is an oversimplification because macrophages possess great plasticity and can be polarized into various phenotypes depending on the antigenic stimuli and cytokines within the local microenvironment [ 8 , 13 ]. These data reveal that macrophage activation states in LN are far more diverse and dynamic, with multiple intermediate and functionally distinct populations beyond the M1/M2 paradigm. The transition from the inflammatory state is phenotypically characterized by expression of Arg-1 and mannose receptors, and upregulation of phagocytic markers such as CD36 and MERTK, which promote apoptotic cell clearance and tissue repair [ 8 ]. M2a macrophages (CD206 + CD68+) are induced by Th2 cytokines, IL-4 and IL-13 [ 14 ]. M2c macrophages (CD163+/CD68+) are induced by IL-10, TGF-β or glucocorticoids [ 15 ]. Although both M2a and M2c macrophages are anti-inflammatory and reparative, their over-accumulation in LN is also associated with fibrosis in LN [ 16 ]. M2b macrophages have a mixed phenotype; they are induced by ICs or other FcR ligands and secrete immunoregulatory IL-10, as well as pro-inflammatory IL-6 and TNFα [ 14 ].
The immune architecture of LN kidneys is further shaped by chemokine-mediated lymphoid cell trafficking. Macrophages as well as epithelial cells play a key role in this process by secreting CXCL12 and CX3CL1, and attracting leukocytes via CXCR4 and CX3CR1 receptors. LN macrophages promote DC recruitment through high expression of CCL2 and CCL8 [ 8 ]. Due to the lack of phenotypic and functional markers, characterization of DCs in LN has been challenging. Analysis of human kidneys from LN patients identified three populations of DCs. pDCs (BDCA-2+) secrete IFNα and drive SLE immunopathogenesis [ 17 ]. DC-SIGN-positive mDCs main autoimmunity and promote tissue damage. Both, pDCs and mDCs also contribute to in situ lymphocyte activation and autoantibody production [ 8 , 18 ]. Lastly, a small population of Langerin-positive DCs was identified, although their role in LN is not yet understood [ 18 ].
Emerging innate lymphoid cell (ILC) and neutrophil populations are also being implicated in LN pathogenesis. Recent studies have identified ILC1s expressing NKp46 in inflamed kidneys, where they contribute to pro-inflammatory macrophage expansion and epithelial injury via GM-CSF; targeting NKp46 in lupus-prone mice reduced tissue inflammation and injury [ 19 ]. Low-density granulocytes (LDGs), a pathogenic neutrophil subset elevated in LN, exhibit increased NET formation and heightened type I interferon secretion. These cells contribute to vascular and tissue damage and may also function as antigen-presenting cells [ 20 , 21 ].
Taken together, macrophages, dendritic cells, ILCs, neutrophils, and chemokine networks establish a highly structured immune microenvironment in LN kidneys, where resident and infiltrating immune cells engage in sustained crosstalk, perpetuating inflammation and shaping disease progression.
Lymphoid compartment
Key lymphoid cell involved in LN are T and B lymphocytes. T cells exhibit diverse phenotypes that control inflammation and autoantibody production. In SLE and LN, aberrant CD4 + T cell receptor (TCR) signaling disrupts peripheral tolerance, and contributes to an accumulation of effector/memory T helper cells (Th) due to impaired PI3/AKT/mTOR signaling, which interferes with T cell elimination through activation-induced cell death [ 22 ]. Furthermore, impaired NF-kB signaling and decreased IL-2 production skews T cell differentiation away from T regulatory (Treg) cell that maintain peripheral tolerance via secretion of TGF-β, toward Th17 subtype [ 23 ] that produces pro-inflammatory cytokines, IL-17 and IL-6. Unlike serum CD4⁺ T cells, which often display clear Th1 and Th17 polarization and association with kidney disease in SLE patients, the renal CD4 + T cell compartment lacks strong lineage-specific cytokine expression, suggesting a more plastic or non-traditional effector phenotype in LN [ 8 , 23 ]. Lastly, extra-follicular helper T cells (T FH ), which express CXCR5, PD-1, ICOS, Bcl-6 and CD40L [ 22 ], support in situ differentiation of autoreactive B cells and autoantibody production.
CD8 + cytotoxic T cells (CTLs) have the ability to kill infected or aberrant cell through the release of cytotoxic proteins such as perforin and granzymes. However, the effector functions of CTLs are impaired in SLE [ 24 ]. Serum CTLs produce less perforin and granzyme B, suggesting reduced elimination of autoreactive cells as well as infections, which is the main cause of mortality in LN [ 6 ]. In contrast to SLE, kidney biopsies from LN patients are enriched in CTLs expressing high levels of PRF1 and GZMB, or GZMK; moreover, the CD8 + T cells also have minimal expression of exhaustion markers, PD-1 and CTLA4, suggesting their sustained cytotoxic activity [ 8 ]. Lastly, double negative T cells, characterized by the lack of cell-surface expression of CD4 and CD8 but sustained TCRαβ expression, contribute to SLE kidney disease where they accumulate and produce the pro-inflammatory cytokine IL-17 [ 24 ]. They are thought to originate from pre-existing CD8 + T cells that undergo lineage transition into double negative T cells, due to chronic stimulation by inundated local tissue antigens [ 25 , 26 ].
B lymphocytes represent a diverse and highly activated compartment in LN kidneys. B cells interact with T FH cells at the T cell-B cell interface in secondary lymphoid organs where the autoantibody production is initiated. Somewhat surprisingly, structures resembling germinal centres with follicular dendritic cells, proliferative T cells and local B cell clonal expansion and somatic hypermutation in reaction to local tissue antigens were observed in kidneys of LN patients [ 8 , 27 ]. The most striking finding is the presence of age-associated B cells (ABCs), a subset associated with chronic activation and autoimmunity. ABCs can be plasma precursors and upregulate expression of CD27, CD86 and IgG1while downregulating other immunoglobulin classes, namely IgD and IgM [ 8 , 28 ]. Furthermore, activation, differentiation and autoantibody production are promoted by B cell-activating factor (BAFF), which may also be secreted intra-renally [ 5 , 12 , 29 ]. Plasmablasts, marked by high XBP1 and MZB1 expression, are also present indicating ongoing differentiation toward antibody-secreting cells locally [ 8 ]. Thus, in situ B cell activation also contributes to overall antibody production and immune complex deposition in LN.
Key signaling pathways in LN
Immune cell interactions in LN are driven by an intricate interplay of inflammatory signaling networks. The activation of FcγR, complement pathways, endosomal Toll-like receptors (TLRs), cytosolic DNA/RNA sensors, JAK/STAT pathway and IFN signature genes represents the earliest upstream events that initiate immune responses in LN.
FcγRs play a critical role in linking autoantibody-mediated immune complex deposition to inflammatory responses in LN. The receptors are expressed on monocytes, macrophages, dendritic cells and neutrophils. They bind to the Fc portion of IgG-containing ICs within renal tissue. Upon engagement, activating FcγRs (e.g., FcγRIIIa) trigger Syk and NF-kB downstream signaling pathways that promote phagocytosis, oxidative bursts and cytokine production. Conversely, the inhibitory FcγRIIb expressed on B cells helps control immune activation. The co-engagement of FcγRIIb and the ITAMs on B cell receptor (BCR) creates a negative feedback loop that decreases antibody production [ 30 ]. Deactivating mutations and deletions in FcγRIIb are associated with development of lupus in both mice and humans. In LN, FcγR activation cooperates with complement pathways to amplify immune cell recruitment and tissue damage, making it a crucial component in disease pathogenesis.
The complement system involves over 30 serum proteins that belong to the innate immune system. The activation of complement involves three pathways, classical, alternative and lectin, which culminate in generation of membrane attack complex (MAC) that “pokes holes” in the cellular membrane causing cellular death. In LN, it is the classical complement pathway that is commonly activated when C1q in the C1 complex recognizes the Fc portion of the antibody (either free or in IC) within renal tissue. Upon Fc binding, C1 complex cleaves C4 and C2 to activate C3 convertase (C4b2a) and ultimately C5 convertase (C4b2a3b) [ 31 ]. C5 cleavage leads to the formation of C5a, which not only recruits C6-9 proteins to assemble into the MAC, but also serves as a potent anaphylatoxin that recruits inflammatory cells to the kidney, exacerbating injury. Excessive complement activation in LN occurs due to presence of autoantibodies and ICs, which are poorly cleared by dysregulated macrophages. Given the close interplay between FcγRs and complement activation, aberrant FcγR signaling can further potentiate complement-mediated inflammation and exacerbate renal damage. To this end, low serum C3 and C4 levels correlate with disease severity. Moreover, deficiencies in C1q or accumulation of anti-C1q antibodies impair the clearance of apoptotic cells, leading to flare-ups that further worsen kidney function [ 32 ].
The accessibility of cell-free nucleic acids and chromatin from apoptotic cells and NETs, activate intracellular nucleic acid sensors, such as endosomal TLRs and cytosolic DNA/RNA sensors [ 33 ]. Endosomal TLRs, more specifically TLR9 and TLR7/8, are expressed by pDCs and B cells. TLR9 recognizes dsDNA, whereas TLR7/8 binds ssRNA; both TLRs activate MyD88 and transcription factors IRF7 and IRF3, which leads to substantial expression of IFN-α and IFN-β cytokines and other IFN-inducible genes. Additionally, cytosolic DNA/RNA sensors , such as cGAS and DAI, activate the STING pathway that also leads to secretion of IFN-α and IFN-β [ 34 , 35 ]. Subsequent binding of IFN-α/β to IFNAR1/IFNAR2 on neighbouring nucleated cells leads to activation of JAK1/TYK2 and STAT1 signaling pathway, activating hundreds of IFN-stimulated genes (ISGs). These genes further enhance proinflammatory response, autoantigen presentation and autoantibody production. Approximately 85% of SLE patients exhibit an “ interferon signature ,” characterized by increased expression of ISGs that are associated with inflammation [ 36 ]. Compared to SLE, where IFN-α is produced primarily by pDCs and neutrophils, LN is characterized by IFN-α production predominantly from renal cells rather than immune cells [ 33 , 37 ].
The complexity of LN is further exemplified by the cellular cross-talk. For example, the convergence of NF-κB and IFN signaling pathways drives the expression of pro-inflammatory cytokines and adhesion molecules, promoting immune cell infiltration into the kidney. IFN-α further enhances NF-κB activation by increasing TLR7 expression, making pDCs and B cells more sensitive to self-RNA-containing immune complexes. Lastly, the interplay between TLR7/TLR9, NF-κB, IFN-I, and JAK-STAT pathways sustains chronic inflammation and renal damage in LN. By disrupting these signaling cascades, novel targeted therapies hold promise in controlling disease progression and preserving renal function.
Targeted therapeutics for treatment of LN
Recent advances in the understanding of LN immunopathogenesis have led to the development of targeted therapies aimed at modulating immune responses. These include monoclonal antibodies (mAbs), small molecule inhibitors, and, more recently, chimeric antigen receptor (CAR) T and NK (CAR-NK) cell therapies. The following section reviews therapies currently under clinical investigation.
Monoclonal antibodies and biologics
Therapies targeting B cells and their survival pathways have transformed the treatment landscape for SLE, with anifrolumab (anti-IFNAR1; targeting B cells indirectly via DCs) and belimumab (anti-BAFF) already approved, and several others in advanced clinical trials (Fig. 2 ; Table 1 ). However, their role in LN is still under investigation. The TULIP-LN phase II trial suggested improved glomerular filtration rate in the anifrolumab-treated group compared to placebo, and indicated that future efficacy trials may need to focus on more intensive therapy for greater benefit [ 38 , 39 ]. This may be due to the underlying differences between SLE and LN disease biology, where the source of IFN-α in LN appears to be renal cells, rather than immune cells [ 33 , 37 ]. Since not all IFN-signature positive patients respond to anti-INF- α therapy, developing predictive biomarkers of therapeutic response is still an area of active research [ 40 ].
Fig. 2 Targeted treatments in clinical development for LN. SMOL = small molecule inhibitor; CAR = chimeric antigen receptor. Created in BioRender. Braunstein, M. (2025) https://BioRender.com/ord9o08 Data last accessed from clinicaltrials.gov on May 5, 2025
Table 1 Targeted therapy trials. Biologics in clinical trials targeting B-cell depletion/survival (top), co-stimulation (middle) and complement pathway (bottom) are shown with their key inclusion/exclusion criteria and key details. Data last accessed from clinicaltrials.gov on May 5, 2025
Table 1
Targeted therapy trials. Biologics in clinical trials targeting B-cell depletion/survival (top), co-stimulation (middle) and complement pathway (bottom) are shown with their key inclusion/exclusion criteria and key details. Data last accessed from clinicaltrials.gov on May 5, 2025
Belimumab was the first biologic approved for SLE, and subsequently for LN, demonstrating moderate clinical benefit by reducing disease flares and steroid dependence [ 41 , 42 ]. However, its efficacy in severe or refractory LN remains limited. Recent clinical studies suggest that combining belimumab with rituximab may offer additive or synergistic effects by targeting distinct B-cell populations, potentially improving renal outcomes. The BEAT-LUPUS trial demonstrated that sequential administration of rituximab followed by belimumab significantly delayed B-cell repopulation and anti-dsDNA antibodies, and reduced disease flares in refractory SLE patients [ 43 ]. This combination strategy is being further explored in ongoing trials (e.g., Synbiose) and may represent a promising approach for improving long-term renal outcomes in patients with difficult-to-treat LN [ 44 ]. Building on the BAFF signaling pathway, newer mAbs such as ianalumab targeting the BAFF receptor (BAFF-R), and dual BAFF/APRIL antagonists like telitacicept and povetacicept, are aiming to more comprehensively suppress B cell survival signals. Ianalumab is being evaluated in phase 3 trial ( NCT05126277 , registration date: 2021-10-15),
whereas telitacicept and povetacicept, which combine a TACI-Ig fusion protein with Fc, are being developed in phase 2 ( NCT05680480 ) and phase 1/2 trial ( NCT05732402 ), respectively. Anti-CD20 antibodies, rituximab and obinutuzumab, are also heavily investigated for their ability to target pathogenic B cells. Despite mixed results in phase III trials, rituximab is widely used off-label [ 45 ]. Post-hoc analysis of the LUNAR trial revealed that complete peripheral B-cell depletion, rather than rituximab use per se, was associated with improved renal responses, emphasizing the role of B-cell kinetics in treatment efficacy [ 46 ]. Furthermore, observational data suggest rituximab efficacy varies by disease phenotype (higher response in class III vs. class IV/V nephritis), and ancestry, with stronger responses noted in patients of African and Latin American descent [ 45 , 47 ].
Obinutuzumab, a glycoengineered anti-CD20 antibody, has shown improved B cell depletion and efficacy in recent trials, NOBILITY and REGENCY [ 48 , 49 ]. Furthermore, anti-CD38 antibodies such as felzartamab and daratumumab, which were originally developed for multiple myeloma, are being repurposed to deplete long-lived plasma cells in refractory lupus patients ( NCT06064929 ; [ 50 ]). Early studies show promise in targeting autoreactive antibody-secreting cells, which escape anti-CD20 therapies.
Other emerging targeted therapeutics focus on co-stimulatory blockade (Fig. 2 ). Abatacept (CTLA-4-Ig), which failed in initial lupus trials has found utility in some cases of refractory LN [ 51 ] and is being evaluated in phase 2 trial ( NCT00774852 ). CD40/CD40L inhibitors, VIB4920 and iscalimab, are also in early-phase clinical trials ( NCT05201469 ; NCT03610516 ), aiming to inhibit pathogenic T-B cell interactions more selectively than global T cell suppression. mAbs against IL-6 (sirukumab; NCT01273389 ) and CD6 (itolizumab; NCT04128579 ) have also entered early clinical development and shown promising results in reducing proteinuria [ 52 ].
Lastly, among complement targeting drugs, ravulizumab (anti-C5 antibody) is entering phase 2 clinical trial for LN ( NCT04564339 ). Ravulizumab acts downstream to prevent MAC formation, which could potentially dampen a broader inflammatory response. On the contrary, complement inhibition may increase susceptibility to infections, which is a significant concern in LN where infection is already a leading cause of morbidity and mortality.
Taken together, mAb reflect a strategic pivot toward more precise immunomodulation, moving beyond general immunosuppression to disrupt pathogenic B, T and plasma cell compartments while preserving broader immune function.
Small-molecule inhibitors
Small molecule (SMOL) inhibitors offer an option to target intracellular antigens and modulate signaling pathways, which are not accessible to mAb-based therapeutics. Voclosporin, a novel calcineurin inhibitor, gained FDA approval in 2021 after demonstrating benefit over SOC [ 53 ]. Additionally, JAK inhibitors (JAKi) have emerged as potent immunomodulators in lupus by blocking cytokine signaling downstream of type I and II cytokine receptors [ 54 , 55 ]. Unlike biologics that target individual cytokines, JAK inhibitors can modulate multiple inflammatory pathways simultaneously. Filgotinib, a selective JAK1 inhibitor, is being explored for lupus based on its favorable safety profile relative to pan-JAK inhibitors ( NCT03285711 ) [ 56 ]. By sparing JAK2 and JAK3, filgotinib may reduce risks of immunosuppression, addressing some of the key safety concerns in a lupus population already prone to infections. Another SMOL in clinical development includes laquinimod ( NCT01085097 ), which modulates NF-κB activity and innate immune responses [ 57 ]. This molecule is being investigated in lupus for its ability to reduce pro-inflammatory cytokine production and immune cell trafficking. Lastly, zanubrutinib, which is a selective Bruton tyrosine kinase (BTK) inhibitor that targets B cell and myeloid activation, is also being repurposed for clinical development in lupus ( NCT04643470 ), after being approved for various B cell cancers. Zanubrutinib offers a promising strategy to target both autoantibody production and innate inflammation without full B cell depletion [ 58 ]. Together, these SMOLs reflect a growing shift toward oral, multi-targeted therapies that could complement or replace injectable biologics in LN disease management, with the potential for broader immunologic impact.
Cell-based therapies
In parallel with mAbs, chimeric antigen receptor (CAR) cell therapies have emerged as a powerful, though still experimental, approach to treating severe autoimmune disease. Initial case reports and early phase clinical studies of CD19-directed CAR-T cells have demonstrated remarkable clinical responses in patients with refractory SLE, often resulting in prolonged drug-free remission. These responses, first reported in 2021, have now been replicated in small cohorts across multiple academic centers [ 59 , 60 ]. A landmark case series reported on 15 patients with severe autoimmune diseases, including eight with SLE, treated with CD19-directed CAR T-cell therapy. Remarkably, all SLE patients achieved clinical remission with sustained resolution of disease activity, normalization of serologic markers, and complete withdrawal of immunosuppressants over a median follow-up of 15 months [ 61 ].
A key advantage of CAR-T approaches in autoimmunity is their potential to “reset” the immune system through deep, sustained B cell depletion, unlike mAbs that often require chronic administration. The results from CD19 CAR-T cell trials provide a compelling rationale for further CAR cell therapy development in SLE and LN. To that end, CD20 CAR-T cells, while still under preclinical or early clinical development, may offer a complementary or safer profile by targeting a narrower window of B cell development. In addition, efforts are underway to engineer BCMA-directed CAR-T cells to target plasma cells [ 62 ]. Meanwhile, CD19 CAR-NK cells may offer a safer alternative to CAR-T cells, although most CAR-NK cells are still in preclinical development or early-phase trials ( NCT06557265 ; NCT06255028 ) (Table 2 ).
Table 2 Cell therapy trials. CAR-NK (top) and CAR-T (bottom) cell therapies examined in clinical trials are shown with their key inclusion/exclusion criteria and key details. Data last accessed from clinicaltrials.gov on May 5, 2025
Table 2
Cell therapy trials. CAR-NK (top) and CAR-T (bottom) cell therapies examined in clinical trials are shown with their key inclusion/exclusion criteria and key details. Data last accessed from clinicaltrials.gov on May 5, 2025
Across these platforms, ongoing challenges include optimizing dosing to balance efficacy and manage potential side effects such as cytokine release syndrome (CRS) and effector cell-associated neurotoxicity syndrome (ICANS) in a non-oncologic setting. CRS is a life-threatening inflammatory response that leads to uncontrolled cytokine release and potentially, multi-organ failure. ICANS involves neurologic symptoms, like confusion and seizures. Furthermore, in autoimmune diseases, sustained CAR-T cell activity may not be ideal as prolonged depletion of normal immune cells could lead to immunosuppression. Newer strategies are exploring ways to limit or control CAR expression through molecular on/off switches allowing for more precise tuning of CAR-T cell persistence and targeting to improve safety and reduce long-term toxicity [ 63 , 64 ]. Additionally, long manufacturing timelines often spanning three to five weeks, combined with the high costs associated with individualized cell therapies pose significant barriers to scalability and patient access. In oncology, the total cost of CAR-T treatment can exceed $400,000–$500,000 USD per patient, with additional expenses related to hospitalization and management CRS [ 65 ]. These hurdles raise important questions about feasibility and equitable access to cell therapy as CAR-T/NK therapies expand into autoimmune indication.
Despite these challenges, the early success of CAR therapies in autoimmunity has galvanized interest, and several academic and industry-sponsored trials are now underway ( NCT06708845 ; NCT06925542 ; NCT06121297 ; NCT06294236 ; NCT06152172 ; NCT05798117 ; NCT06752876 ; NCT06544330 ) (Table 2 ). If these therapies continue to demonstrate durability and safety, they may redefine treatment paradigm for LN in the next decade.
Future directions
Unlocking new pathways for immunomodulation
As our understanding of lupus nephritis (LN) deepens, attention is shifting toward more nuanced mechanisms that govern immune dysfunction. As illustrated in Fig. 2 , most of the treatments in clinical development focus on elimination of pathogenic lymphocytes or inhibition of proinflammatory cytokines. However, emerging data from immunophenotyping and scRNA-seq consistently highlight myeloid cells, and less lymphocytes, as the most abundant and functionally significant contributors to LN flare-ups. This disconnect between mechanistic insights and therapeutic targeting underscores a critical gap in current therapeutic strategies.
Recent research on metabolic reprogramming of immune cells, such as alterations in glycolysis and oxidative phosphorylation, is helping define proinflammatory versus regulatory phenotypes of macrophages, as well as T cells, within the renal microenvironment. Targeting the metabolic checkpoints, such as mTOR, AMPK and HIF-1α, is an area of growing interest. To this end, inhibitors of mTOR have shown promise in preclinical models, where mTOR blockade enhances AMPK and prevents the progression of LN [ 66 , 67 ]. In addition, blockade of glycolysis or genetic depletion of HIF-1α in macrophages that have undergone a switch to glycolysis in response to activation by IgG ICs, modulates glycolytic flux and attenuates hypoxia-driven inflammation [ 68 ]. These strategies offer a potential path for nuanced targeting of IC-activated M1a and M2b macrophages, without inducing broad immunosuppression.
Lastly, epigenetic regulation via DNA methylation, histone modifications and non-coding RNAs has emerged as a critical modulator of immune gene expression in LN. Aberrant DNA methylation in T cells and histone acetylation patterns in renal tissue have been linked to disease flares. Epigenetic therapies, including HDAC inhibitors and methyltransferase blockers, hold potential to reset immune homeostasis with lasting effects [ 69 ].
Non-immunologic therapies
While most investigational therapies in LN target immune dysregulation, there is growing recognition that renal parenchymal cells, such as podocytes and tubular epithelial cells, actively contribute to disease progression through cytokine production, antigen presentation, and injury responses. Podocytes are involved in maintaining the glomerular filtration barrier, and their injury leads to proteinuria. Additionally, podocytes act as antigen-presenting cells by upregulating MHC class I and II molecules and co-stimulatory molecules to prime T cells, as well as playing a role in complement activation [ 70 ]. Therapeutic strategies directly targeting podocytes are emerging. Calcineurin inhibitors, such as cyclosporine and tacrolimus, have shown to stabilize the podocyte cytoskeleton and reduce proteinuria. Similarly, rituximab has demonstrated properties beyond B-cell depletion through podocyte-protective effects, such as maintaining cytoskeletal integrity and reducing apoptosis. Experimental agents targeting podocyte-specific pathways, including TRPC5 channel inhibitors, are also explored in preclinical studies [ 71 , 72 ]. Collectively, these approaches aim to complement immunomodulatory therapies by directly preventing or reversing podocyte damage that drives disease progression in LN.
Similarly, tubular epithelial cells contribute to kidney inflammation and injury through cytokine and chemokine production, recruitment of immune cells, and phenotypic changes that exacerbate tubulointerstitial damage. As such, non-immunologic therapies such as sodium-glucose co-transporter 2 (SGLT2) inhibitors, which act directly on proximal tubular epithelial cells, are also being explored off label for their renoprotective effects. Although their role in LN remains under investigation, early data suggest potential benefit in reducing proteinuria and preserving renal function when added to immunosuppressive regimens in patients with glomerulonephritis [ 73 , 74 ].
Technology-driven discovery
The next frontier of LN research is being shaped by multi-omics technologies. Single-cell and spatial transcriptomics are already revealing the cellular heterogeneity and spatial organization of immune infiltrates in nephritic kidneys. These tools help decipher how specific cell populations, particularly tissue-resident memory T cells or intrarenal B cell aggregates, contribute to disease progression. Proteomics and metabolomics add further resolution by identifying post-translational modifications and metabolic signatures that distinguish active from quiescent disease states. In parallel, advances in machine learning (ML) and artificial intelligence (AI) are revolutionizing biomarker discovery through predictive algorithms trained on multi-omics data, and will likely identify molecular signatures associated with flare-ups and/or therapeutic response [ 75 ]. Such approaches promise to move beyond static diagnostic categories and towards response-adaptive medicine in LN.
Translation of innovation to practice
Realizing the promise of these innovations requires strategic re-design of disease monitoring. Incorporating molecular biomarkers into clinical trial protocols can enable more precise patient stratification and increase the likelihood of therapeutic success. Similarly, monitoring for disease flare-ups should focus on integrating real-time biomarker monitoring so that treatment strategies may also adapt dynamically based on molecular cues, rather than clinical manifestations. Urine-based markers provide a non-invasive window into renal tissue injury and immune activation within the kidney, and offer real-time indicators of local disease activity [ 76 ]. Blood proteomic signatures can identify systemic immune perturbations predictive of impending flares, while transcriptional profiling could capture gene expression programs that distinguish disease states and track shifts in immune activity over time [ 77 , 78 ].
Recent studies combining laser microdissection of LN kidney biopsies with proteomic and serologic analyses have identified IgG2 autoantibodies against nuclear and podocyte antigens, α-enolase and annexin A1, as enriched in the glomeruli of LN patients. These autoantibodies were elevated in serum, correlated with disease activity, and distinguished LN from non-renal SLE, RA and other autoimmune conditions [ 79 – 82 ]. Their decline with therapeutic intervention might provide a potential utility for diagnosis and real-time disease monitoring. Embedding these biomarker strategies into clinical trials and routine disease monitoring could enable more adaptive treatment strategies, shifting the focus from reactive symptom management to proactive, biologically informed care.
Despite these scientific advances, translating biomarker insights into clinical use remains complex. Widely used biomarkers such as anti-dsDNA and complement have limited predictive value for LN flares due to low specificity and sensitivity, and lack of data from large multi-centre trials for validation [ 83 ]. Newer biomarker candidates identified through multi-omics approaches require rigorous validation across diverse patient populations, and differences in disease phenotypes and assays used can affect their reproducibility. In addition, the cost and regulatory pathways associated with implementing molecular diagnostics in routine practice remain significant barriers. Standardizing protocols, building longitudinal datasets, and engaging regulatory agencies early in the development process will be critical steps toward integrating these tools into personalized care.
Lastly, the pace of progress depends on interdisciplinary collaboration. Partnerships between nephrologists, immunologists, bioinformaticians and systems biologists will be vital to translating bench insights into bedside interventions. Platforms for data sharing, standardization and cross-validation will accelerate the conversations between discovery and clinical practice to translate breakthroughs in renal immunology into benefit for patients with LN.
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Author contributions
MB wrote the manuscript and prepared figures. The author wrote the manuscript, created all figures and tables, and made revisions.
Funding
The author received no funding support.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethical approval
This article is a review and does not contain any primary studies with human participants or animals; as such, ethics approval was not required for this manuscript.
Clinical trial registration
The study is not a clinical trial; clinical trial number is not applicable. The author had no access to the clinical trials referenced in the paper; all clinical trial information was obtained from publicly available data on clinicaltrials.gov. The consent was not required for this manuscript.
Competing interests
The authors declare no competing interests.
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