SLE is a severe autoimmune disease characterized by a loss of immune tolerance, culminating in the immune system’s attack on the body’s healthy cells and tissues. This leads to immune complex-mediated inflammation across various organs, including the heart, kidneys, and skin (23). The mortality rate of patients with SLE is approximately 2–3 times higher than that of the general population, with geographical variations in prevalence and a female-to-male ratio of about 9:1 (24), affecting certain ethnic groups disproportionately, such as African Americans, American Indians, and Asians (25). The primary factors of mortality in SLE patients include renal disease, cardiovascular disease, and infections. Despite the approval of three novel treatments for SLE and lupus nephritis in recent years, the therapeutic management for the majority of patients has seen minimal evolution since the last century, with long-term outcomes characterized by high morbidity and mortality (26).

The complex immunopathogenesis of SLE encompasses a multitude of factors including genetics, environment, hormonal influences, epigenetics, and immune modulation, all of which can impact the immune system either individually or in concert (24). A key aspect of this complexity is the impaired clearance of apoptotic cells, which leads to the accumulation of cellular debris ( Figure 2 ). This debris can activate normally dormant autoreactive lymphocytes, potentially evading self-tolerance under conditions of recurrent or chronic stimulation (27). Furthermore, neutrophils, particularly low-density granulocytes, may exacerbate the intricate interplay between innate and adaptive immune responses. Through increasing the production of pro-inflammatory cytokines and forming neutrophil extracellular traps that contain immunostimulatory proteins and self-antigens, such as double-stranded DNA, the inflammation is perpetuated (28). In addition to these cellular mechanisms, the IFN-1 signaling pathway, which mimics a sustained antiviral response, is associated with lupus susceptibility and may amplify the autoimmune reaction. This amplification can be manifested by the enhancement of autoreactive humoral activity. Genome-wide association studies (GWAS) have identified at least 132 lupus susceptibility loci (29). The functional significance of these variants and their potential role in lupus expression remain largely unknown. Additionally, sex hormones and environmental influences may contribute to immune system dysregulation in genetically predisposed individuals (5). Current therapeutic approaches include glucocorticoids, immunosuppressants, and belimumab, which often fail to achieve drug-free remission.

MS is the most prevalent chronic inflammatory disease of the central nervous system (CNS) and the most common nontraumatic disabling condition affecting young individuals, impacting over 2 million people worldwide. It affects females at a ratio of approximately 3:1 and remains incurable. The majority of patients are diagnosed between the ages of 20 and 40, although children and the elderly can also be diagnosed with MS (30). Typical presenting syndromes of MS include, but are not limited to, monocular vision loss due to optic neuritis, limb weakness or sensory loss due to transverse myelitis, diplopia resulting from brainstem dysfunction, or ataxia caused by cerebellar lesions (31). MS can manifest as an inflammatory disorder characterized by episodes of neurological symptoms followed by partial or complete remission (relapsing-remitting MS, RRMS, in 85% of cases), or as a progressive disease (primary progressive MS, PPMS). Over time, RRMS may evolve into a progressive phase of the disease known as secondary progressive MS (SPMS) (32).

It remains unclear whether MS is attributable to a single cause or a combination of factors, as few specific triggers have been identified. Epstein-Barr virus (EBV), ultraviolet B (UVB) radiation, cigarette smoking, and vitamin D, in conjunction with an individual’s genetic background, all play significant roles in the development of MS. The prevalence of MS increases with latitude, a gradient closely related to UVB exposure, which stimulates the production of vitamin D in the skin. Low levels of vitamin D, reduced dietary intake of vitamin D, decreased outdoor activity, and increased susceptibility to MS associated with genetic polymorphisms linked to low vitamin D levels all correlate with the pathogenesis of MS (33). Furthermore, genetic factors influence susceptibility to MS, as approximately one-eighth of patients have a family history of the disease (34). GWAS conducted on samples collected from thousands of MS patients and matched controls have identified over 200 genetic variants that elevate the risk of developing MS, with the most significant association being linked to the HLA-DRB1*1501 haplotype (32).

RA is an organ-specific autoimmune disease primarily characterized by symmetric peripheral polyarthritis. It may also affect other organs, including the lungs, heart, blood vessels, skin, and eyes (35). The patients typically present with symmetric polyarthritis of the hands and/or feet, which can progress to joint destruction if left untreated (36). In individuals diagnosed with RA, there is often an overlap with other diseases or comorbidities, including cardiovascular disease, chronic lung disease, and periodontitis (37). RA affects approximately 0.5% to 1% of the global population, with a higher prevalence in regions farther from the equator, and the prevalence in women is two to three times greater than that in men. RA is classified as an autoimmune disease due to the presence of autoantibodies, such as rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPAs), in most cases (38).

The etiology of RA remains unknown; however, certain risk factors are associated with an increased likelihood of developing the condition. These factors include the family history of RA or other autoimmune diseases, smoking, poor dental health, and viral infections. Several infectious agents are recognized as potential pathogens or promoters of RA, including EBV, retroviruses, bacterial superantigens, and mycoplasmas, as well as specific microorganisms such as Porphyromonas gingivalis and Prevotella intestinalis. The pathogenesis of RA is complex, with genetic susceptibility playing a crucial role. First-degree relatives of individuals with RA take a risk of developing the disease that is 2 to 5 times greater than that of the general population (39). GWAS conducted on a large scale have identified more than 100 loci associated with RA (40), including TNIP2, WISP1 and TNFRSF11A (41), and these alleles increase the risk of the disease and dramatically affect immune pathways. The most relevant alleles include the “common epitope” (SE) on the HLA-DRB1 locus and protein tyrosine phosphatase (PTPN22) (42).

GWAS have unveiled shared genetic variations across multiple diseases, providing crucial clues for understanding the genetic foundations of autoimmune diseases conditions. By GWAS analysis, researchers have identified some common genetic markers for SLE, MS, and RA. Variant in the HLA region is particularly prominent in these diseases; as a key component of the human leukocyte antigen system, the polymorphisms of HLA genes are closely associated with susceptibility to autoimmune diseases (41). Specifically, the presence of HLA-DRB1*04:01 and HLA-DQB1*03:01 alleles significantly increases the risk of RA in individuals and promotes the development of an autoimmune response by affecting autoantigen presentation and T-cell responses. Additionally, specific variations in the PTPN22 gene, which is involved in the regulation of T-cell signaling, have been shown to be associated with an increased risk of various autoimmune diseases, including SLE and RA (29, 43). STAT4 plays a key role in Th1, Th17, and Tregs, and the single-nucleotide polymorphisms (SNP) rs7574865 for STAT4 is associated with increased risk of SLE and RA (44). The TNFSF13B gene, which is involved in the survival and differentiation of B cells, has variations that are associated with an increased risk of SLE (45). The IRF5 gene plays a role in the immune response, and several SNPs (rs4728142, rs2004640, rs1744583) and small insertions/deletions in the IRF5 gene or regulatory regions have been validated to independently cause SLE, MS and RA by altering gene expression, splicing, and RNA stability (46) These findings indicate that although SLE, MS, and RA have different clinical manifestations, there is a genetic overlap, which may reflect common mechanisms in their immune regulatory pathways. The outcomes of GWAS are of significant importance for elucidating the complex genetic structure of autoimmune diseases, advancing the development of precision medicine, and developing new therapeutic approaches.

Autoimmune diseases exhibit a pronounced sexual dimorphism, with a higher incidence rate among females than males for numerous conditions. This gender bias may stem from a convergence of factors, including sex chromosome disparities, hormonal influences, the activity of the Xist ribonucleoprotein complex, gender-based immune cell variations, environmental exposures, and genetic predispositions. The presence of two X chromosomes in females could contribute to distinct immunomodulatory gene expression patterns, as the X chromosome is enriched with such genes, and variations in X chromosome number may influence susceptibility to autoimmune diseases (47). Men with Klinefelter syndrome (XXY) have an extra X chromosome, which causes them to experience significant impairments in fetal germ cell (FGCs) development, such as stagnation of FGCs at an early age, abnormal dosage of X-linked genes, aberrant interactions of Sertoli cells with FGCs, and inhibition of the TGF-β signaling pathway to improve FGCs differentiation (48). Disturbances in these molecular mechanisms not only affect their reproductive health, but are also associated with an increased risk of autoimmune diseases. Patients with KS may have abnormalities in their immune system, including abnormalities in the number and function of immune cells and a chronic inflammatory state, which together may put them at higher risk for autoimmune diseases (49). Recent studies have further revealed how abnormalities in gene dosage on the X chromosome can affect the risk of autoimmune diseases, particularly in patients with KS. The extra X chromosome leads to increased expression of X-linked genes such as Tlr7, a single-stranded RNA sensor associated with the pathogenesis of autoimmune diseases. Research has found that in KS patients, the X chromosome does not undergo inactivation in FGCs, resulting in an excess of X-linked gene dosage, which may directly impact the function of immune cells and the regulation of autoimmune responses. Additionally, a 3.2MB region of the X chromosome has been translocated to the Y chromosome, and this previously unreported X-Y translocation may influence the risk of autoimmune diseases in KS patients (50). These findings underscore the importance of X chromosome dosage control for maintaining normal immune function and provide a new perspective on how gender affects the pathogenesis of autoimmune diseases, highlighting the significance of gender differences in autoimmune disease research. Additionally, fluctuations in sex hormones like estrogen and progesterone may perturb immune cell development and activity, disrupting immune tolerance. The Xist RNP complex, responsible for X chromosome silencing in females, also forms molecular complexes implicated in autoimmune pathogenesis (51). Furthermore, environmental factors such as infections and ultraviolet radiation may impact the immune system in a gender-specific manner, and certain genetic variants are more prevalent in women, potentially increasing their risk for autoimmune diseases. The interplay among these factors likely drives the higher incidence of autoimmune diseases in women, highlighting the complexity of sex-based differences in disease susceptibility.

Tregs constitute 5-7% of CD4+ T cells and develop both directly in the thymus (thymus-derived Tregs, tTregs) and in peripheral tissues (peripherally-derived Tregs, pTregs). They possess the ability to suppress immune responses and promote tissue repair, ensuring that the immune system maintains a proper balance between its responses to foreign antigens and self-antigens (63). Treg cells are located in inflamed tissues and localized secondary lymphoid organs, where they exert their immunosuppressive functions. The number and functionality of Treg cells are altered in autoimmune diseases, resulting in defects in immune tolerance, abnormalities in immunoregulation, increased inflammation, and the proliferation of autoimmune cells. Treg cells confer immune tolerance through various mechanisms, including the secretion of anti-inflammatory soluble mediators such as interleukin-10 (IL-10), transforming growth factor-beta (TGFβ), and interleukin-35 (IL-35). They also achieve this by depleting interleukin-2 (IL-2) and expressing cytotoxic T lymphocyte antigen 4 (CTLA-4), CD39, CD73, and other inhibitory cell-surface receptors (64). Furthermore, Tregs regulate the direct or indirect targeting of T cells by APCs. For instance, the binding of CTLA-4 to CD80/CD86 on APCs induces the enzyme indoleamine-2,3-dioxygenase (IDO) (65). Additionally, Treg binding to APCs can result in the removal of cell surface molecules (a process akin to phagocytosis), thereby altering co-stimulation and antigen presentation (66).

Several therapeutic strategies based on the function of Treg cells have been proposed to restore tolerance in affected tissues. Transcription factors in Treg cells play a pivotal role in maintaining immune tolerance, preventing autoimmunity, modulating immune responses, promoting immune homeostasis, and supporting transplantation tolerance. Forkhead box P3 (Foxp3) plays a crucial role in the differentiation, development, and functional stabilization of Tregs. Fluctuations in Foxp3 protein levels can alter the stability of Treg function. Such variations are associated with a spectrum of significant immune-related disorders in humans. These include infectious diseases, autoimmune diseases, allergic diseases, tumorigenesis and metastasis, as well as transplant rejection. The Foxp3 gene has thirteen mutations, including five within the forkhead domain, one causing a frameshift due to a nucleotide deletion, and another disrupting the leucine zipper domain through base deletion. Such mutations may destabilize the mRNA, resulting in reduced levels of normal Foxp3 protein in T cells. This can lead to immune-mediated disorders such as diabetes, lymphadenopathy, and cytokine storms in vivo ( 67). The therapeutic potential of Foxp3+ Tregs has been demonstrated in various preclinical models such as graft-versus-host disease (GVHD) (68), type 1 diabetes mellitus (T1D) (69), systemic lupus erythematosus (70), inflammatory bowel disease (71) and multiple sclerosis (72). Currently, over 50 clinical trials are either underway or have been completed to assess the safety and efficacy of Treg cell therapy for the treatment of conditions such as renal or liver transplantation, atypical forms of pemphigus, systemic lupus erythematosus, inflammatory bowel disease, autoimmune hepatitis, allergies, and asthma (73).

Treg cells play a crucial role in suppressing immune responses and maintaining immune homeostasis. The infusion of polyclonal Treg cells has demonstrated a favorable safety profile. The efficacy of this approach has been established in patients with type 1 diabetes mellitus and those with GvHD, with additional clinical trials currently underway for patients with Crohn’s disease and aspergillosis. IL-2 is a vital factor in promoting Treg cell expansion by regulating the STAT5 signaling pathway and enhancing Foxp3 expression, which is essential for Treg cell function and proliferation (74). Consequently, IL-2 analogs, such as IL-2/antibody complexes and IL-2 mutant proteins, represent promising therapeutic strategies for treating autoimmune diseases. In August 2013, a phase I/IIa study (NCT02084238) led by Peking University People’s Hospital showed that the administration of low-dose IL-2 has been shown to stimulate Treg cell expansion of patients with various autoimmune conditions involving (75). Amgen’s AMG-592, an IL-2 mutein with increased regulatory T cell selectivity, is in phase I/II trials in systemic lupus erythematosus and graft-versus-host disease, which also showed enhanced Treg cell expansion after low-dose IL-2 infusion in patients with SLE and type 1 diabetes (76) However, the limitations of IL-2 therapy include its short half-life, the necessity for repeated injections, and the potential for anti-drug immune responses. To address these challenges, Treg cells have been engineered, including those with transgenic TCRs or CARs, which have shown improved efficacy in targeting specific antigens and suppressing effector responses compared to polyclonal Treg cell infusion.

MSCs are pluripotent progenitor cells capable of supporting hematopoiesis and differentiating into various mesodermal cell lineages, such as osteoblasts, chondrocytes, and adipocytes (77). They possess significant repair potential through self-renewal and differentiation and are increasingly recognized for their ability to modulate the immune response, exhibiting immunomodulatory properties. MSCs are believed to play a crucial role in the formation of memory T-cell and B-cell survival niches in the bone marrow and interact effectively with a variety of myeloid and innate leukocytes, including dendritic cells, monocytes, and macrophages (78). This interaction modulates immune memory size, stability, and plasticity. Initially, MSCs were found to inhibit mitogen-induced T-cell proliferation in vitro and evade immune surveillance in vivo. Subsequent studies have demonstrated that MSCs can modulate immune responses during chronic inflammation by regulating cell recruitment, function, and fate within the innate and adaptive immune systems (79). Following extensive in vitro and in vivo preclinical trials, both autologous and allogeneic MSCs have been utilized in the treatment of various immune-mediated diseases, including graft-versus-host disease, Crohn’s disease, multiple sclerosis, refractory systemic lupus erythematosus, and systemic sclerosis.

It is now established that autoreactive T lymphocytes, particularly CD4/helper T cells, play a crucial role in the development of autoimmune diseases. A significant finding across most autoimmune conditions is the imbalance between the effector T-cell subsets Th1/Th17 and Tregs, which produce the immunomodulatory cytokine IL-10. This imbalance ultimately leads to inflammation and damage in target tissues. Given that the immunomodulatory effects of MSCs have been shown to be most effective on CD4+ T cells, it is not surprising that MSCs have been utilized in the highest number of clinical trials aimed at treating autoimmune diseases. Currently, over 25% of MSC-related trials focus on autoimmune conditions; these 129 trials include 34 for inflammatory bowel disease (IBD), 25 for multiple sclerosis, 18 for type 1 diabetes, 16 for systemic lupus erythematosus, 12 for RA, 9 for psoriasis, and 15 for other autoimmune diseases. The majority of these trials are in the early phases, with 29 in phase I, 15 in phase II, and 73 in combined phases I/II. Additionally, there are seven ongoing trials assessing efficacy, including three in combined phases II/III, three in phase III, and one in phase IV. Furthermore, five trials have not yet been assigned a phase (80).

In a comprehensive analysis by Zeng et al (81), the therapeutic efficacy and safety of MSC transplantation were evaluated across five autoimmune diseases, encompassing 18 randomized controlled trials. Among patients with RA, a trio of trials by Yang et al (82) indicated that MSC treatment led to reduced disease activity, enhanced standing time over 50% alleviation in knee pain, and decreased medication reliance, with benefits persisting up to 12 months in the majority of cases. In the context of SLE, four randomized controlled clinical trials assessed parameters such as urinary protein levels, serum complement C3, and adverse events following MSC intervention. These trials revealed lower urinary protein levels and alongside elevated serum C3 levels in the treatment group compared to the control group, with no significant adverse events reported across all studies (83). Six trials concerning MS demonstrated that patients who received MSC therapy exhibited superior progression-free survival (PFS), a reduced total number of episodes, and without encountering any severe adverse events (84).

The core pathological characteristic of autoimmune diseases is the aberrant attack of the immune system on self-tissues, leading to chronic inflammation and tissue damage. This conundrum of immune dysregulation has prompted the medical community to explore alternative cellular therapies, aiming to reset or rebalance the immune system and restore tolerance to self-antigens. In this field, HSCs have emerged as ideal candidates for the treatment of autoimmune diseases due to their unique immunomodulatory properties (85, 86). HSCs are capable of repopulating the immune system, reducing the number of autoreactive lymphocytes, and by secreting cytokines such as TGF-β and IL-10, they modulate the immune microenvironment, fostering the formation of an anti-inflammatory milieu (87). Furthermore, HSCs can differentiate into Tregs and other immunomodulatory cells, which play a crucial role in suppressing autoimmune responses.

Based on these mechanisms, hematopoietic stem cell transplantation (HSCT) has been established as a standard therapeutic approach for malignant hematological disorders, other oncological conditions, and severe immunodeficiencies (88). For patients with autoimmune diseases who have an inadequate response to conventional treatments, HSCT following high-dose chemotherapy is increasingly being utilized in clinical practice. The therapeutic principle of HSCT involves initial lympholysis to reduce the immune memory repertoire, including autoreactive clones, followed by a profound immune renewal through the regeneration of hematopoiesis and the immune system (10). This process not only offers patients the opportunity to rebuild their immune system but also provides the possibility for long-term remission of autoimmune diseases. In 2012, it was estimated that approximately 3,000 patients with autoimmune diseases worldwide received HSCT treatment (89). As clinical research progresses, the application prospects of HSCT in the treatment of autoimmune diseases are expected to expand further.

HSCT has demonstrated significant potential in addressing severe, refractory SLE. Multiple research outcomes have indicated that HSCT can markedly improve the disease prognosis for SLE patients while reducing their reliance on long-term immunosuppressive drug therapy. Since its initial application in the treatment of SLE in 1997, over 300 cases of autologous hematopoietic stem cell transplantation have been reported globally (90). Furthermore, autologous HSCT has shown positive effects in patients with aggressive MS, not only facilitating the recovery of neurological functions but also successfully halting the disease’s progression. For patients with RA unresponsive to conventional therapies, HSCT treatment has achieved long-term remission of the condition. In 1996, the first case of autologous HSCT for a patient with rheumatic autoimmune disease was reported (91); the patient, who faced rejection for lung transplantation due to connective tissue disease and severe pulmonary arterial hypertension, ultimately benefited from HSCT. To date, more than 3,000 HSCT procedures have been conducted worldwide for patients with severe rheumatic and non-rheumatic autoimmune diseases (87). These data underscore the efficacy and feasibility of HSCT in treating certain autoimmune diseases, offering new directions for future therapeutic approaches.

HSCT offers a potentially transformative approach for the treatment of autoimmune diseases but still faces challenges such as GVHD, infection risks, donor matching difficulties, conditioning regimen toxicity, graft failure, and long-term complications. However, with the advent of non-myeloablative conditioning regimens, improved HLA typing techniques, gene-editing technologies, the development of new anti-rejection drugs, the expansion of indications, and the emergence of “off-the-shelf” stem cell products, the prospects for HSCT are continuously improving. This evolution provides patients with safer, more effective, and more accessible treatment options, expected to enhance long-term survival rates and quality of life.

With the inherent ability of T cells to infiltrate tissues, their high-affinity binding to specific targets, and their antitumor effector functions, CAR-T cell therapy is predicated on the precise targeting of tumor antigens, resulting in the lysis and destruction of tumor cells. CAR-T cells offer several advantages over monoclonal antibodies, as T cells are long-lived, capable of proliferation, can be transported to lymphoid tissues or target organs, and can develop memory populations that help prevent the recurrence of disease-causing lymphocytes (92). Zelig Eshhar first demonstrated a CAR prototype in 1982, which shares many conceptual similarities with the CAR structures used today (93). The cytoplasmic portion of the CAR includes signaling domains (the CD3ζ chain of the T-cell receptor) and costimulatory domains (such as 4-1BB or CD28) to ensure the proper expansion and activation of CAR-T cells, as well as the proliferation of target cells. The CD19 antigen, expressed by B-cell-derived malignancies such as lymphomas and leukemias, was the first clinically applicable target for cancer immunotherapy using autologous CAR-T cells (94).

CAR-T cells demonstrate significant potential in the treatment of autoimmune diseases due to their ability to eliminate pathologically activated immune cells and to reestablish immune tolerance in organs affected by immune dysregulation. The number of studies investigating the use of CARs for treating autoimmune diseases is rapidly increasing ( Table 1 ), with a particular focus on CAR-T cells and T cells (95). In 2021, CAR-T cells targeting CD19 were first utilized to treat a 20-year-old woman with severe treatment-refractory SLE (96). This approach confirmed the feasibility of producing CAR-T cells from patients with autoimmune diseases, and patient compliance with CAR-T cell infusions like this is high without any serious toxic reactions. This marked the first CAR-T cell-based treatment for an autoimmune disease, and additional clinical trials using anti-CD19/BCMA CAR-T cells or anti-CD19 CAR-T cells for relapsed/refractory SLE are currently ongoing (97). Using CD19-targeted CAR-T cell therapy, some researchers successfully treated a patient with anti-synthetase antibody syndrome, who fully recovered from the autoimmune disease without the need for immunosuppressive medications six months after CAR-T cell therapy (98). Over the past two years, CAR-T cells have also been employed in preclinical trials for MS, type 1 diabetes mellitus, inflammatory bowel disease, SLE, and pemphigus vulgaris (PV) suggesting new hope for therapeutic options in autoimmune diseases (99). In RA, one study designed CAR-T cells to eliminate specific autoreactive B cells by citrullinating antigenic epitopes, resulting in the lysis of B-cell subsets (100). Additionally, another study constructed CD8 T cells expressing the HLA-DR1 CAR, which led to a reduced CD4 T cell response and inhibition of autoantibody production, indicating the potential for a highly specific therapeutic approach in the treatment of autoimmune diseases (101).

The expression of CAR in Tregs represents a promising strategy to enhance the efficacy and specificity of Treg therapy. Researchers have developed CAR-Tregs that target carcinoembryonic antigen (CEA) for the treatment of ulcerative colitis (UC). These anti-CEA CAR-Tregs specifically inhibited colitis symptoms in various experimental UC models using the colons of CEA transgenic mice (102). In a landmark study, researchers engineered CAR-Tregs against 2,4,6-trinitrobenzene sulfonic acid (TNBS) in a mouse model of colitis (103). CAR-Tregs secrete inhibitory factors, proliferate, and ameliorate disease symptoms in an antigen-specific manner. Similar findings have been reported in mouse models of multiple sclerosis and transplant rejection (104–106). CAR-Tregs demonstrate therapeutic efficacy at doses comparable to those of non-engineered Tregs, indicating that CAR expression not only enhances the efficacy of Treg therapy but also increases its specificity. Overall, these studies provide a robust theoretical foundation for clinical trials of CAR-Treg therapy.

Transient mRNA-based CAR-T cell therapy has emerged as a promising approach for the treatment of autoimmune diseases. Conventional CAR-T cell therapies utilize lentiviral or γ-retroviral vectors to introduce permanent genetic modifications to T cells, which carry risks of genotoxicity and regulatory challenges. Additionally, CAR-T cells may persist for a lifetime (107). Given that the safety standards for autoimmune trials are exceptionally high—often exceeding those for cancer trials—mRNA-based CAR-T cell therapies present an alternative strategy for delivering CAR-encoded mRNAs to T cells without permanently altering their genomes. This method allows for transient, time-limited expression of CARs, providing a controlled and reversible therapeutic approach. In a phase 1b/2a clinical study, mRNA-based CAR-T cell therapy demonstrated the potential for more durable symptomatic relief of myasthenia gravis and was well tolerated, with no significant adverse effects reported in patients (108). However, the potential immune response to CAR-T cells, the need for precise dosing and treatment timing, and the requirement for Good Manufacturing Practice (GMP)-compliant drug manufacturing have yet to be fully addressed in this rCAR-T cell study.

In the context of malignant diseases, the risk of immune escape, along with tumor recurrence and toxic effects, represents one of the most significant limitations of CAR-T cell therapy Cytokine release syndrome is particularly concerning as a toxic effect of CAR-T cell therapy; mild cases may present with symptoms such as fever, headache, arthralgia, and myalgia, but severe cases can lead to hypotension and even cytokine storm. Another common side effect is immune effector cell-associated neurotoxicity syndrome, which can manifest as fine motor deficits, resulting in writing difficulties and altered speech. Additional symptoms associated with immune effector cell-associated neurotoxicity syndrome include headache, confusion, seizures, and behavioral changes. Therefore, further basic and preclinical studies are essential to evaluate CAR-T cell-based therapies.

Significant success has been reported in the use of anti-CD19/anti-CD19 BCMA CAR-T cells for the treatment of cancer and SLE. However, these approaches result in the depletion of all B cells in the body (109). Consequently, B cells may be absent for weeks to months, leaving patients immunocompromised during this period. To address this widespread B-cell depletion, researchers have developed CAARs that specifically and precisely target pathogenic B-cell subsets. Therapeutic T cells are genetically modified with chimeric receptors that incorporate target antigens for autoantibodies as extracellular structural domains. Unlike CAR-T cells, which express molecular receptors found on pathological cells, CAAR-T cells express extracellular autoantigens recognized by the B-cell receptor (BCR) (110). This extracellular structural domain is linked to the transmembrane structural domain, the costimulatory structural domain, and the activation structural domain, similar to the intracellular components of CARs.

Autoantigen recognition by autoreactive B cells leads Autoantigen recognition by autoreactive B cells leads to the activation of CAAR-T cells and the specific lysis of pathogenic B cells. Findings from a preclinical mouse model of atypical pemphigus suggest that CAAR-T cells expressing Desmoglein 3 may be effective in treating the rare skin disease known as pemphigus vulgaris (99). In a recent study, researchers developed a novel therapy for the most prevalent form of autoimmune encephalitis, specifically NMDA receptor encephalitis (110). Programmed CAAR-T cells are designed to recognize and eliminate anti-NMDA receptor antibody-producing B cells with high precision, and this innovative approach demonstrated its efficacy in a mouse model. Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disorder characterized by life-threatening muscle weakness due to the presence of anti-MuSK autoantibodies, which disrupt neuromuscular junction signaling. Researchers engineered T cells expressing the MuSK chimeric autoantibody receptor with a CD137-CD3ζ signaling domain (MuSK-CAART) to specifically target B cells that produce anti-MuSK autoantibodies (111). In an experimental autoimmune MG mouse model, MuSK-CAART effectively reduced anti-MuSK IgG levels without affecting overall B-cell counts or total IgG levels, indicating the selective depletion of MuSK-specific B cells. While CAAR-T cell approaches have shown promise in treating various autoimmune disorders, their development is limited to diseases caused by single autoantibody-producing monoclonal B-cell clones.

A total of six CAR-T cell therapies have been approved to date, demonstrating significant promise primarily for the treatment of hematological malignancies. However, this approach is effective only in a subset of patients and is associated with considerable side effects, such as cytokine release syndrome and neurotoxicity, which further limits its broader application in cancer treatment (112). To address these limitations, researchers have turned their attention to NK cells, which are integral to the innate immune response—the body’s first line of defense against infections—and play crucial roles in antiviral, anticancer, and anti-aging processes. NK cells, along with T and B cells, form a major subset of lymphocytes capable of nonspecific, non-MHC-restricted direct tumor cell killing (97). NK cells are pivotal in cancer immunity as they target cancer cells that downregulate HLA class I molecules or express stress markers. Furthermore, NK cells can be genetically modified to express CARs and can be utilized without the need for recipient-matched human leukocyte antigens, thereby eliminating the necessity for patient-specific production of CAR products. One study demonstrated that lupus-like mice treated with CAR-NK cells exhibited improved splenomegaly and a reduction in the number of PD-1+CD4+ T cells (113). Additionally, a clinical phase 1/2 trial involving umbilical cord blood-derived NK cells expressing an anti-CD19 chimeric antigen receptor and IL-15 (cAR19/IL-15) was conducted with 37 patients suffering from CD19+ B-cell malignancies. The results indicated that none of the patients developed neurotoxicity or graft-versus-host disease, and only one patient experienced cytokine release syndrome (grade I) (114). These findings underscore the feasibility of utilizing CAR-NK cells for cancer treatment.

According to previous studies, there exists an innate lymphocyte population derived from NK cells known as tissue-resident memory natural killer (NKRM) cells. These cells play a crucial role in regulating immune responses within tissues by preventing the immune system from mistakenly attacking its own tissues or organs, thereby helping to avert autoimmunity (115). Researchers have preliminarily demonstrated that NKRM cells exhibit distinct immune functions compared to traditional memory cells; they can eliminate CD4+ T cells, reduce autoimmunity in a TRAIL-mediated manner, and may hold significant potential for research into the treatment of SjD (115). The results of this study revealed that four patients with severe disease achieved deep remission after treatment with these cells, transitioning from “severe” to “mild” disease, with corresponding durability. Additionally, two patients with severe disease attained deep remission after just 15 days of treatment, with SLEDAI-2K disease scores decreasing from 14 and 17 points (indicating severe disease) to 1 and 3 points (indicating mild disease), respectively. This indicates a highly positive effect of CAR-NK cell therapy. This study represents the first international clinical report on the use of CAR-NK cells for the treatment of SLE.