Autoimmune diseases are a heterogeneous group of disorders caused by the misdirection of the immune system toward its host, and the presence of autoantibodies is a common feature of autoimmune diseases (1). There are nearly 100 different types of autoimmune diseases in humans, some of these are organ-specific, such as type 1 diabetes (T1D), while others are systemic, such as systemic lupus erythematosus (SLE) (2). Autoimmune diseases, previously considered rare, affect approximately 5%–8% of the world population according to epidemiological studies (3).

Given the limited understanding of the complex molecular mechanisms underlying autoimmune diseases, it is widely accepted that a combination of genetic predisposition and environmental factors disrupts immune tolerance (4–6), This disruption leads to the clonal expansion of autoreactive B and T cells, resulting in the production of autoantibodies that trigger autoimmune inflammation and the pathological attack on the body’s tissues. Current standard approaches offer no cure; rather, they focus on lifetime management. The primary approach for treating autoimmune diseases continues to involve controlling autoreactive T and B cells that attack host tissues, typically through the use of broad immunosuppressive agents such as glucocorticoids, methotrexate, and azathioprine (7–9). Recent advances have introduced a new paradigm of interventions, including biological agents and targeted small molecules, which more specifically inhibit detrimental immune cells and modulate specific inflammatory pathways. However, many patients with autoimmune diseases eventually relapse and may suffer from life-threatening complications (3). In summary, while current treatments can manage symptoms, they generally lack curative potential and are often associated with significant toxic side effects, some of which can be life-threatening. This highlights the urgent need for more optimized and curative therapies.

Chimeric antigen receptor (CAR) is a fusion protein consisting of an antigen recognition domain and a cell activation domain that can redirect T cell specificity, function, and metabolism (10). In oncology, CAR T cells have been used to accurately identify and eliminate cancer, showing remarkable and lasting efficacy in the treatment of certain cancers, particularly leukemia, lymphoma, and multiple myeloma (11–13). A decade-long follow-up study demonstrated that CAR T cells can persist in leukemia patients for up to ten years post-treatment, correlating with sustained disease remission and prolonged B-cell aplasia (14). Originally developed for cancer therapy, this approach mediates durable elimination of autoreactive B cells in autoimmune diseases, potentially eliminating the need for chronic immunosuppression. Importantly, it may also reestablish immune tolerance through secondary modulation of pathogenic T cell responses. Through this mechanism, CAR T-cell therapy, which targets autoreactive immune cells, is increasingly emerging as a potential curative approach for autoimmune diseases (15–18). It should be noted that CAR T-cell therapy is not intended to entirely replace existing treatment strategies. Instead, it is more appropriately positioned as a potential later-line option for patients with autoimmune diseases who exhibit inadequate responses to conventional therapies—including biological agents—or who are unable to tolerate their associated toxicities, particularly in cases of refractory or relapsing diseases. Recent preclinical studies, along with case reports and small-scale clinical trials, have yielded promising results in the treatment of autoimmune diseases using CAR T-cell therapy (19, 20). This review will focus on the clinical needs and applications, advantages and limitations, proposed solutions, and prospects of CAR T-cell therapy in the context of autoimmune diseases.

For clinical practitioners, autoimmune diseases are generally categorized into two main types: systemic and organ-specific. This classification is straightforward and practical, but its value in guiding treatment is limited, particularly as it does not reflect the underlying causes and immune mechanisms of the diseases. Therefore, a more precise classification based on specific pathogenic immune responses (such as abnormal T cell or B cell-mediated reactions) is beneficial for formulating personalized treatment plans. Characteristics of pathogenic immune responses include selective dysregulation of T cells or B cells, as well as dysregulated immune responses to specific self-antigens. For instance, in organ-specific diseases (such as T1D and thyroiditis), T cells play a crucial role, while in systemic diseases, such as SLE and rheumatoid arthritis (RA), B cells and their antibodies dominate. This classification method is beneficial in clinical treatment, as different immune mechanisms may require distinct therapeutic strategies ( Table 1 ).

The pathogenesis of autoimmune diseases involves a complex interplay between genetic susceptibility and environmental factors, with T cells and B cells collaboratively triggering and maintaining abnormal immune responses, forming an autoimmune cycle that ultimately leads to chronic inflammation and tissue damage (21) ( Figure 1 ). Systemic autoimmune diseases, such as SLE and RA, exhibit widespread activation of the immune system, affecting multiple organs and tissues, and their pathogenic mechanisms involve self-antigen exposure and immune complex deposition (22). In these diseases, dendritic cells (DCs) present self-antigens to T cells (23), leading to the activation of T cells that secrete cytokines such as IL-21 and IFN-γ (24), which further activate B cells. Activated B cells undergo affinity maturation and differentiation into plasma cells, producing autoantibodies targeting a wide range of antigens (25). These autoantibodies bind to free molecules and antigens to form immune complexes, which can deposit in the vascular walls and tissues of multiple organs, triggering inflammation and damage (26). The deposition of immune complexes and the resultant local inflammatory responses establish an autoimmune cycle, continuously stimulating the activation of T cells and B cells, thereby exacerbating tissue damage and inflammation (27). Once this autoimmune cycle is initiated, if not interrupted by pharmacological intervention, the abnormal immune response persists, leading to the long-term maintenance and progression of autoimmune diseases (28).

In contrast, organ-specific autoimmune diseases, such as T1D and Graves’ disease, primarily target specific organs and involve immune responses against specific organ self-antigens. In these diseases, specific antigens, such as islet β-cell antigens or thyroid antigens, are presented to T cells by local antigen-presenting cells (APC), including DCs and macrophages. Activated T cells then attack the cells within the target organ by secreting specific cytokines like IL-17 and IFN-γ (29). For instance, in T1D, cytotoxic T cells directly attack islet β-cells, resulting in insufficient insulin secretion; in Graves’ disease, autoantibodies stimulate thyroid receptors, leading to hyperthyroidism (30, 31). These autoantibodies and local inflammatory responses create a specific immune cycle, which, unlike systemic diseases, is primarily confined to the affected organ (32).

In both systemic and organ-specific autoimmune diseases, the mechanism commonly involves the abnormal activation or dysregulation of T cells and B cells. This abnormal activation not only initiates the immune response but also sustains the pathological progression, forming an autoimmune cycle that makes the disease difficult to reverse (33, 34). Understanding this mechanism is crucial for developing effective treatment strategies. Although traditional therapies can alleviate symptoms and control disease activity, completely disrupting the autoimmune cycle remains a challenge (22, 35).

Current treatments for autoimmune diseases mainly include corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-inflammatory drugs (DMARDs), biologics, and targeted small molecules. Despite the variety of therapeutic options available, many patients are still predominantly treated with non-specific conventional treatments, with corticosteroids being among the most commonly used drugs. Corticosteroids can rapidly alleviate symptoms due to their powerful and broad anti-inflammatory and immunosuppressive effects. However, corticosteroids are a double-edged sword. Long-term or high-dose use can lead to serious complications, such as secondary infections, gastrointestinal ulcers, and femoral head necrosis, which can significantly impact patients’ quality of life and even be life-threatening (36–39). To reduce the cumulative dose of corticosteroids, DMARDs with steroid-sparing effects are often utilized. These include methotrexate, leflunomide, tacrolimus, azathioprine, mycophenolate mofetil, hydroxychloroquine, and cyclophosphamide (40–45). While DMARDs can help decrease the need for corticosteroids and lower the risk of disease relapse, patients in remission generally require lifelong low-dose maintenance therapy to prevent relapse. Furthermore, DMARDs do not offer targeted immunosuppressive effects; instead, they broadly inhibit various immune pathways, which can affect multiple cells in the body and increase the risk of secondary diseases, such as cancer (46).

Researchers are working to develop new treatments that are more effective, specific, and safer. Recently developed and clinically applied biological agents, such as various monoclonal antibodies and targeted small molecules like Janus kinase (JAK) inhibitors, have shown promise as treatment options for many autoimmune diseases, including SLE, RA, multiple sclerosis, myositis, psoriasis, atopic dermatitis, and pemphigus, without causing life-threatening adverse reactions (47, 48). The emergence of these novel drugs has alleviated some of the current treatment challenges and brought new hope to patients. For example, the anti-CD20 monoclonal antibody rituximab has demonstrated efficacy in several autoimmune diseases and has received marketing authorization for use in patients with SLE, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris (49). Belimumab, another biological agent used to treat SLE, works by inhibiting B cell survival and differentiation into antibody-producing plasma cells through the blockade of B-cell activating factor (BAFF) (50). Additionally, the targeted small molecule upadacitinib, a JAK inhibitor, blocks the phosphorylation of downstream effector proteins, thereby inhibiting cytokine signaling in key inflammatory pathways in immune cells. It has been approved for the treatment of RA and psoriatic arthritis (51).

Unfortunately, while these novel drugs can effectively attenuate the inflammatory process, they often require continuous treatment over many years or even a lifetime. Despite achieving remission, disease recurrence is common when immunosuppression is discontinued. This may be due to immune escape mechanisms that prevent the complete eradication of autoimmunity in patients with autoimmune diseases. Studies demonstrate that autoreactive B cells persist in specific tissue compartments after rituximab therapy, including SLE tonsils, systemic sclerosis skin lesions, and RA synovium (52–55). These findings suggest that, compared to circulating B cells, memory B cells in tissues are more resistant to depletion. Notably, these remaining tissue-resident B cells are thought to be responsible for disease relapse (53, 56).

Current treatments for autoimmune diseases rely mainly on systemic immunosuppression, which generally reduces disease activity and can slow progression in many patients. However, this approach often requires ongoing medication. Prolonged use of immunosuppressive therapies can lead to side effects and complications, with some patients developing refractory disease states that are difficult to manage effectively.

Researchers have been striving to develop therapies capable of “resetting” the immune system, with the goal of profoundly recalibrating immune balance, terminating disease activity, and allowing patients to achieve long-term remission without the need for continued immunosuppressive therapy. In 1993, Marmont A. M. first proposed hematopoietic stem cell transplantation (HSCT) for severe, refractory lupus patients (57). This idea soon extended to severe autoimmune diseases (58, 59) and has been considered an alternative for SLE patients unresponsive to standard treatments (60). Multiple clinical trials suggest HSCT can induce long-term remission in various autoimmune diseases without maintenance therapy (61, 62). However, despite its advantages, the high rate of adverse effects, such as infections and secondary autoimmune diseases (63, 64), has limited HSCT’s use in autoimmune conditions like SLE (65). Further research is needed to assess the efficacy and safety of HSCT as a promising option for treating autoimmune diseases.

Dendritic cell (DC) therapy, a promising new immunotherapy that has made strides in cancer treatment (66), has recently been applied to autoimmune diseases (67). Through tolerogenic DCs, this approach induces immune tolerance in T cells against self-antigens, thereby suppressing autoreactive T cells in autoimmune disease management (68). Currently, DC therapy is in preclinical and early trials, demonstrating potential in inducing antigen-specific immune tolerance, thereby modulating T-cell responses and alleviating disease progression in RA (69), T1D (70) and multiple sclerosis (71). Despite this potential, challenges remain, including generating stable and functional DCs ex vivo and designing personalized DC vaccines tailored to diverse disease mechanisms. Further large-scale trials are required to validate its long-term efficacy and safety.

The application of natural killer (NK) cell therapy in autoimmune diseases remains in an early exploratory phase. NK cells can regulate the immune system by cytokine secretion and interacting with other immune cells (72, 73), modulating the activity of T cells, DCs, and macrophages, which impacts immune tolerance and inflammatory responses (72, 74). Consequently, NK cells show potential in suppressing autoimmune responses and restoring immune balance. Preclinical studies demonstrate that in vitro expansion and activation of NK cells effectively reduce inflammatory responses and improve clinical symptoms in the experimental autoimmune encephalomyelitis (EAE) model (75, 76). However, challenges persist, including precise control of NK cell activity to avoid damage to normal tissues, ensuring long-term stability, and optimizing applications across different autoimmune diseases. Despite these challenges, NK cell therapy’s immunomodulatory capacity and low toxicity present a promising therapeutic avenue for future treatment strategies.

Significant progress has been made in applying gene editing therapies to autoimmune diseases, primarily by modifying immune cell functions to inhibit pathological immune responses. The CRISPR/Cas9 gene editing technology, with its high efficiency, specificity, and flexibility, has been widely used to regulate T cells, B cells, and regulatory T cells (Treg cells), aiming to reduce their attack on self-tissues and restore immune tolerance. With technological advances, these approaches have shown promise in treating diseases like SLE, RA, and multiple sclerosis (77, 78). By targeting pathogenic genes or immune regulatory pathways, CRISPR/Cas9 holds promise for achieving personalized treatment and offers a novel strategy for precise intervention in autoimmune diseases. However, the long-term follow-up data on CRISPR/Cas9 gene editing technology remain limited, making it impossible to completely rule out potential long-term risks. The challenges of clinical translation and limitations of delivery systems further restrict the application of CRISPR/Cas9 in autoimmune diseases. Additionally, its high cost, ethical concerns, and the complexity of personalized treatment continue to limit widespread clinical application.

These therapies each have their advantages and limitations, and the most suitable option should be selected based on the patient’s disease characteristics, severity, and treatment goals. However, HSCT faces high risks and costs. Both DC and NK cell therapies are still in the early stages, and the long-term sustainability of their efficacy remains to be verified. Gene editing therapies, while precise, face ethical controversies and challenges related to personalized treatment. Recently, the development of engineered receptors has rapidly advanced CAR T-cell therapy (79). Initially applied to hematologic malignancies, CAR T-cell therapy has now been explored for autoimmune diseases. Early clinical applications have shown good safety and efficacy in diseases such as SLE and myasthenia gravis (80–82). Studies suggest that CAR T-cell therapy can target and eliminate pathogenic B cells, effectively control disease activity, and significantly reduce relapse risk, demonstrating potential for a cure (83). These initial successes have laid the foundation for expanding CAR T-cell therapy to a broader range of autoimmune diseases, gradually making it a preferred emerging therapy in the field. This review will focus on the prospects of CAR T-cell therapy in autoimmune diseases.

While CAR T-cell therapy shows great therapeutic promise, it is also associated with serious toxicities, particularly CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), which have become major safety challenges in clinical applications. CRS is the most common adverse event following CAR T cell infusion. It is triggered by the robust activation of CAR T cells and other immune effector cells, leading to a massive release of inflammatory cytokines such as IL-6, IFN-γ, and TNF-α (172). Clinical manifestations range from fever, hypotension, and hypoxia to severe multi-organ dysfunction. The American Society for Transplantation and Cellular Therapy (ASTCT) has proposed a grading system to standardize the assessment of CRS. The risk and severity of CRS are influenced by tumor burden, CAR construct design, and T cell dose. ICANS is another severe toxicity, which often occurs after or concurrently with CRS but can also develop independently. Its pathogenesis involves cytokine-mediated endothelial activation, increased blood-brain barrier permeability, and neuroinflammation (172). Patients may present with confusion, language impairment, seizures, or even cerebral edema. A hallmark of ICANS is the rapid onset of neurological symptoms, typically within one week after infusion.

Currently, tocilizumab, an IL-6 receptor antagonist, is the first-line treatment for CRS and can rapidly alleviate symptoms without compromising the efficacy of CAR T cells. Glucocorticoids are used for moderate to severe CRS and for ICANS, particularly when tocilizumab proves ineffective. Due to its limited ability to cross the blood-brain barrier, tocilizumab is less effective for ICANS, making glucocorticoids the mainstay of treatment. Current preventive strategies primarily include preemptive IL-6 blockade, individualized adjustment of CAR T cell dosage, and the incorporation of “safety switches” into the CAR construct, such as suicide genes that allow for the elimination of CAR T cells when necessary (173). In addition, to reduce the risk of prolonged immune activation, transient CAR expression systems using mRNA transfection or externally controllable CAR designs represent promising directions for therapeutic optimization (174).

As CAR T-cell therapy is progressively applied to autoimmune diseases, patients in this population often present with long-standing immune dysregulation and chronic inflammatory backgrounds, which may render them more susceptible to CAR T-related toxicities. Therefore, establishing a comprehensive toxicity management system is of critical importance. The integration of risk stratification and early intervention into a refined management framework holds promise for enhancing the overall safety of CAR T-cell therapy while maintaining its therapeutic efficacy.

For autoimmune diseases treated with CAR T-cell therapy, risk stratification—based on disease type, severity, immune status, and clinical characteristics—enables personalized treatment optimization to maximize efficacy. Since CAR T-cell therapy may trigger CRS and immune effector cell-associated neurotoxicity syndrome, risk stratification would help identify high-risk patients in advance and implement preventive measures to reduce adverse effects (175, 176). Furthermore, stratified management optimizes resource allocation by prioritizing patients with the highest predicted benefit, improving therapeutic success rates while enhancing safety through personalized risk mitigation (177).

For stratified management of CAR T-cell therapy in autoimmune diseases, patients can be categorized into B cell-mediated and T cell-mediated subtypes based on disease pathogenesis. This stratification approach enables precise treatment strategies tailored to distinct autoimmune subtypes, potentially enhancing efficacy while minimizing adverse effects. B-cell-mediated diseases, such as SLE and RA, are primarily driven by autoantibody production from B cells. Anti-CD19 CAR T cells can target and eliminate CD19-positive B cells, thereby reducing autoantibody production and inhibiting disease progression. In SLE patients, anti-CD19 CAR T-cell therapy induces profound B cell depletion, leading to reduced autoantibody titers and subsequent mitigation of tissue damage (81). Furthermore, CAAR T cells are specifically engineered to selectively target pathogenic B cell subsets while preserving the function of normal B cells, thereby reducing the side effects associated with long-term immunosuppressive drugs (124). For T cell-mediated diseases, such as T1D and multiple sclerosis, the pathology is mainly driven by autoreactive T cells. CAR Treg cells promote immune tolerance by suppressing autoreactive T cell activity, thereby attenuating inflammation and halting tissue damage (141).

In CAR T-cell therapy for autoimmune diseases, stratified management based on disease severity might help optimize treatment outcomes and reduce risks. For mild to moderate patients, low-dose CAR T-cell therapy is typically considered only when conventional immunomodulatory strategies prove ineffective or cause significant side effects. This approach could allow for gradual adjustment of the immune response, preventing overt immunosuppression (178). However, for severe or refractory patients who are unresponsive to standard therapies, CAR T-cell therapy might be used as a last resort to control systemic inflammation and organ damage by eliminating pathogenic immune cells. This treatment carries a higher risk of side effects, necessitating strict monitoring to prevent complications such as CRS (179, 180).

In CAR T-cell therapy for autoimmune diseases, individualized stratified management based on patient age and immune status would be crucial. Younger patients are typically able to tolerate higher doses of CAR T-cell therapy, which might result in more significant outcomes. In contrast, elderly patients, facing challenges such as immune senescence and comorbidities, would require lower doses of CAR T cells and strict monitoring for adverse effects to enhance safety (181, 182). Patients with normal immune function would be suited for standard treatment protocols, whereas those with impaired immune function, such as those on long-term immunosuppressive therapy or with immunodeficiency, might need tailored treatment adjustments to optimize efficacy and minimize side effects (183). All patients require continuous monitoring and adjustment of therapeutic strategies to ensure both safety and efficacy.

The conditioning chemotherapy is a critical element in CAR T-cell therapy, designed to maximize the therapeutic potential of CAR T cells by promoting their proliferation, persistence, and efficacy within the patient’s body. It functions by depleting immunosuppressive Treg cells and myeloid-derived suppressor cells, as well as increasing the availability of key serum cytokines, such as IL-15 and IL-7, which further enhance CAR T cells activity and durability (177, 184). Additionally, conditioning chemotherapy reduces the existing lymphocytes in the patient’s body, creating a “space” for the infused CAR T cells to better proliferate and survive (185). In certain cases, it can also contribute to a reduction in the tumor burden, thereby enhancing the antitumor activity of CAR T cells (186).

The conditioning chemotherapy regimens currently used for autoimmune diseases are primarily adapted from those established for cancer treatment. In CAR T-cell therapy for cancer, common regimens include cyclophosphamide monotherapy, a combination of cyclophosphamide with fludarabine, or bendamustine monotherapy. Cyclophosphamide is generally reserved for specific cases or for patients who cannot tolerate more intensive regimens, and it is infrequently used as monotherapy (177). The cyclophosphamide-fludarabine combination chemotherapy regimen has been widely used in multiple clinical trials and has become the standard conditioning regimen for CAR T-cell therapy. The combined use of cyclophosphamide and fludarabine is believed to more effectively reduce immunosuppressive cells, thereby aiding in the expansion and long-term survival of CAR T cells. Compared to cyclophosphamide alone, the cyclophosphamide-fludarabine combination regimen has been shown to improve CAR T cells expansion and clinical outcomes (187, 188). Bendamustine, as an alternative option, is occasionally employed in patients who cannot tolerate the cyclophosphamide-fludarabine combination. Studies suggest that bendamustine can achieve comparable CAR T cells expansion but may reduce adverse effects, such as neutropenia, though its use is less common (189). In the context of autoimmune diseases, conditioning chemotherapy regimens for CAR T-cell therapy are often derived from those used in cancer but are adjusted in terms of drug selection and dosing. The cyclophosphamide-fludarabine combination regimen has shown promise in autoimmune disease patients, such as SLE, where it effectively reduces disease-driving autoreactive B cells and facilitates an immune system “reset” (81, 124). However, bendamustine is generally not recommended for use in autoimmune disease patients due to its potential for high toxicity, severe immunosuppression, and the lack of safety and efficacy data in this population (172, 175). Therefore, the cyclophosphamide-fludarabine combination is considered a safer and more effective conditioning regimen for autoimmune diseases and is more commonly recommended in clinical practice.

The conditioning regimen for CAR Treg therapy in autoimmune diseases differs from that of conventional CAR T-cell therapy, as CAR Treg cells are designed to enhance immune suppression to prevent autoimmune responses, rather than to eliminate B cells. Therefore, the selection of the conditioning regimen must be carefully considered to avoid impairing Treg cells’ function. Kanakry et al. showed that posttransplantation cyclophosphamide selectively preserved and promoted the reconstitution of Treg cells. This effect is primarily attributable to the high expression of aldehyde dehydrogenase (ALDH) in Treg cells, which metabolizes acrolein—a toxic metabolite of cyclophosphamide—thereby conferring resistance to cyclophosphamide in Treg cells (190). This characteristic suggests cyclophosphamide as an ideal preconditioning regimen for CAR-Treg therapy. Nevertheless, in autoimmune disease patients—many of whom are women of reproductive age—cyclophosphamide presents a concern due to its potential impact on fertility, necessitating careful evaluation (191, 192).

Bendamustine, due to its potent immunosuppressive effects, may impede the expansion and persistence of CAR Treg cells, potentially compromising therapeutic efficacy. Consequently, its application in CAR Treg therapy is generally limited (175). However, the necessity of pre-treatment chemotherapy for CAR Treg therapy in autoimmune diseases remains a topic of debate. Some studies suggest that pre-treatment chemotherapy may enhance the expansion and persistence of CAR Treg cells, while others raise concerns about introducing unnecessary toxicity and risk. As a result, pre-treatment chemotherapy is not universally required for all CAR Treg therapies, and decisions regarding its use should be made with caution, tailored to individual patient needs (193, 194).

The traditional CAR T-cell therapy process is complex and highly personalized, requiring the collection, genetic modification, and expansion of T cells from the patient, which results in long treatment cycles and may be accompanied by disease progression. In patients with autoimmune diseases undergoing immunosuppressive therapy, T-cell function is often suppressed, limiting the collection and expansion of autologous CAR T cells, thereby affecting the efficiency or yield of the final product, with a manufacturing failure rate of 2-10% (195). Moreover, the time-consuming processes of manufacturing, testing, and release, along with the logistical challenges of transporting cells between the treatment site and production facilities, pose significant risks, especially for patients with rapidly progressing or severe conditions. A pressing concern is that two major challenges currently hinder the clinical translation and large-scale trials of CAR T-cell therapy in autoimmune diseases: limited accessibility and high treatment costs. On the one hand, the therapy heavily relies on individualized cell manufacturing, complex genetic engineering platforms, and advanced cell therapy centers, making it difficult to implement routinely in most healthcare institutions. On the other hand, the high costs associated with production, quality control, and regulatory management result in overall treatment expenses far exceeding those of conventional therapies, imposing a significant burden on patients and healthcare systems. Therefore, reducing costs and improving accessibility have become critical bottlenecks that must be addressed to advance the broader application of CAR T-cell therapy. Therefore, the development of allogeneic CAR T technology offers a potential solution to overcome the limitations of traditional CAR T-cell therapies.

Allogeneic CAR T cells, also known as “off-the-shelf” CAR T cells (196, 197), are generated by genetically modifying T cells from healthy donors, enabling rapid therapeutic availability without the need to collect, process, and expand the patient’s own cells. Compared to the complex and individualized manufacturing process of autologous CAR T cells, allogeneic CAR T cells streamline the introduction of multiple cell modifications and achieve product standardization through donor selection and processing. This production approach significantly reduces costs through industrialization and large-scale manufacturing, allowing the generation of a substantial number of CAR T cells from a single donor. Furthermore, the production method for allogeneic CAR T cells enables the batch cryopreservation of T cells, ensuring treatments are readily available for patients. This approach not only saves resources and time but is particularly critical for patients with severe and acute conditions, as it meets their urgent need for timely therapeutic interventions (196). Additionally, the batch manufacturing of allogeneic CAR T cells facilitates the reuse of products when needed, providing a convenient option for retreatment. Most patients undergoing CAR T-cell therapy have been on long-term immunosuppressive treatments (such as corticosteroids, cyclophosphamide, tacrolimus, and rituximab) to control their condition, which can severely impair T cell quantity and function. As a result, the collection and expansion of autologous CAR T cells may be restricted, leading to the production of insufficient quantities or quality of autologous CAR T cells for treatment (196, 198). In such cases, using T cells from healthy donors to produce allogeneic CAR T cells becomes an ideal alternative. This approach not only provides a sufficient quantity of functionally robust T cells but also avoids the issue of suboptimal treatment outcomes due to the patient’s own T cells being functionally deficient or insufficient in number (199, 200). Compared to the personalized process of producing autologous CAR T cells, the production of allogeneic CAR T cells allows for scaling and standardization, significantly reducing costs, saving resources and time, and enabling coverage of a broader patient population (196). Moreover, allogeneic CAR T cells sourced from healthy donors can reduce the number of autoreactive cells in the patient’s body, thereby lowering the risk of relapse. For patients with autoimmune diseases, using allogeneic CAR T cells may also reduce treatment-related side effects, such as CRS (200, 201).

Although CAR T-cell therapy has demonstrated remarkable efficacy in the treatment of tumors and autoimmune diseases, it still faces challenges such as off-target effects, including non-specific attacks on healthy cells (175, 202). For instance, while eliminating pathogenic immune cells, CAR T cells may inadvertently attack normal immune cells, disrupting immune homeostasis or causing adverse effects such as CRS and organ damage. Off-target effects can also damage normal cells, reducing CAR T cell functionality and viability, thereby compromising therapeutic efficacy and increasing risks. The CRISPR/Cas9 gene-editing technology holds promise for enhancing the safety and efficacy of CAR T-cell therapy by mitigating off-target effects and non-specific actions.

Studies have shown (203–205) that directly delivering pre-assembled Cas9/gRNA ribonucleoprotein (RNP) complexes into cells allows Cas9 to rapidly exhibit activity. The rapid degradation of RNP significantly shortens Cas9’s duration of action, effectively reducing the probability of off-target cleavage while maintaining efficient and precise target editing. The combination of CRISPR/Cas9 gene-editing technology with RNP delivery strategy enables precise genome editing in CAR-T cells, thereby enhancing the specificity of target antigen recognition and reducing the risk of non-target antigen misrecognition that may lead to reduced efficacy or disease relapse. Additionally, this strategy facilitates multiplex gene editing and significantly reduces the risk of CRISPR off-target effects due to the transient activity characteristic of RNP delivery (206). In vitro experiments demonstrated that knocking out the SHP-1 gene in CD133-targeted CAR T cells significantly enhanced their cytolytic efficacy against CD133-positive glioblastoma cells. No Cas9 insertion or notable off-target effects were observed, confirming the potential of CRISPR/Cas9 technology to improve CAR T cell precision and reduce off-target effects (207). In a phase I open-label study targeting B-cell acute lymphoblastic leukemia, CRISPR/Cas9 technology was used to construct universal CD19/CD22 dual-targeted CAR T cells. The study enrolled six patients and employed high-fidelity CRISPR/Cas9 editing to knock out the TRAC and CD52 genes. Results demonstrated that the technology achieved high precision without observable off-target effects, while the treatment exhibited favorable safety and significant efficacy (208). By enhancing the specificity, persistence, and functional potency of CAR T cells, CRISPR/Cas9 gene-editing technology is expected to provide critical scientific evidence and technical support for the development of safe and effective CAR T-cell therapies for autoimmune diseases.

CAR T-cell therapy for autoimmune diseases is still in the early stages of clinical trials. While the results are promising, they are limited to a small number of patients, and long-term follow-up will reveal all potential safety issues. It is important to emphasize that these results are preliminary and require further investigation with longer durations and larger patient populations. A report by Mackensen et al. (81) on the use of anti-CD19 CAR T cells in 5 patients with refractory SLE showed that the patients tolerated the treatment well, with only mild CRS. Immature B cells reappeared on average 110 ± 32 days after CAR T cell infusion, and during a longer follow-up period (median (range) 8 (12) months post-CAR T cell administration), the patients remained in drug-free remission. Although this study report demonstrates that CAR T cells have the potential for long-term remission and good tolerability, it is important to consider that SLE patients may accumulate autoantibodies for several years before showing clinical symptoms. Therefore, even in cases of residual or re-emerging potential immune dysregulation, there could still be persistent clinical remission (209). Current studies have relatively short follow-up periods (typically ranging from a few months to about a year) and involve a small number of cases. To better evaluate the long-term effects and safety of CAR T-cell therapy, extended follow-up (five to ten years) is necessary to observe long-term remission rates, disease relapse rates, and potential delayed side effects. Special attention should be given to the chronic toxicity that CAR T-cell therapy may cause, including damage to internal organs, chronic inflammation, or fibrosis (175, 180). CAR T-cell therapy for autoimmune diseases requires further large-scale clinical studies to validate these preliminary results. Besides, long-term monitoring of patients’ immune system status is essential, with particular emphasis on the quantity, types, and functionality of regenerated B cells, as well as changes in T cell subsets, to assess the duration and quality of immune system reconstitution.

In autoimmune diseases, persistent inflammatory responses are compounded by pathological processes including autoimmune attacks, immune complex deposition, vasculitis, and tissue fibrosis, all of which can cause irreversible organ damage (210, 211). Even successful CAR T-cell therapy may fail to reverse established organ damage in autoimmune diseases, as demonstrated by SLE-related glomerulosclerosis, pulmonary fibrosis in systemic sclerosis, exocrine gland fibrosis in Sjögren’s syndrome, and demyelinating lesions in multiple sclerosis. This limitation highlights the critical importance of early intervention during the reversible disease phase. Initiating CAR T-cell therapy before irreversible structural changes occur can significantly improve treatment response rates and preserve long-term organ function.

Combined CAR T-cell therapy is emerging as an important approach for treating autoimmune diseases. In recent years, clinical research has explored the combined use of CAR T cells targeting different antigens, such as CD19 and BCMA, aiming to enhance therapeutic efficacy and overcome the limitations of single-target therapies. This strategy not only effectively eliminates various types of pathogenic cells but also has the potential to improve durability and breadth of treatment through multiple mechanisms. Preliminary clinical data demonstrate that BCMA-CD19 compound CAR T-cell therapy is safe and effective in patients with SLE (87). It not only induces medication-free remission but also significantly reduces pathogenic autoantibodies, showing potential for reducing relapse risk and achieving immune reconstitution. Additionally, combining CAR T with CAAR T offers new possibilities for future research. Anti-BCMA CAR T-cell therapy targets and eliminates pathogenic plasma cells, while CAAR T precisely target abnormal B cells responsible for autoimmune reactions. Their combination may generate synergistic effects, comprehensively clearing pathogenic cells and restoring B cell homeostasis. Although combination therapies show great promise, current research is still in its early stages. Future studies should focus on evaluating their safety, tolerability, and efficacy, as well as addressing potential immune responses and side effects induced by treatment. Overall, combined CAR T-cell therapy offer a novel therapeutic approach for autoimmune diseases, warranting further exploration and clinical validation.

It is noteworthy that most current CAR T-cell therapies primarily target B cells, particularly CD19⁺ B cells and their pathogenic plasma cell derivatives. However, the pathogenesis of many autoimmune diseases is not solely B-cell driven but heavily dependent on T cells—especially CD4⁺ helper T cells reactive to the same autoantigens. The generation of long-lived plasma cells typically requires T-cell help, and the autoantibodies they secrete are antigen-driven. Therefore, even if pathogenic B-cell populations are eliminated, residual autoreactive CD4⁺ T cells may reinitiate the activation of newly regenerated B cells, leading to the re-emergence of pathogenic autoantibodies and increasing the risk of disease relapse. To address this concern, future CAR T-cell strategies may benefit from incorporating approaches that also target autoreactive T cells—such as the development of CAR T cells specifically directed against pathogenic T-cell subsets, or combinatorial strategies involving CAR-Tregs to promote immune tolerance. Furthermore, longitudinal monitoring of CD4⁺ T-cell subsets and their antigen specificity following therapy will be essential to assess whether true immune reprogramming has been achieved. Therefore, optimizing CAR T-cell therapies for autoimmune diseases will require advances in target precision, understanding of autoantigen-driven responses, and elimination of immunological memory to improve long-term efficacy and minimize relapse risk.

To ensure the standardization and normalization of the treatment process, and to enhance patient safety and treatment efficacy, it is essential to establish global consensus guidelines for CAR T-cell therapy in autoimmune diseases. Given the complexity of CAR T-cell therapy for autoimmune conditions, which involves extensive multidisciplinary knowledge, detailed guidelines are needed to direct clinical practice. This will help standardize treatment procedures and reduce variability. Moreover, it will provide clear standards for treatment and side-effect management, ensuring patients receive optimal care while minimizing treatment-related risks. By developing consensus guidelines, multidisciplinary collaboration can be promoted, evaluation standards for treatment efficacy and side effects can be unified, and treatment strategies can be optimized, thereby improving overall safety and effectiveness. Furthermore, such guidelines can advance scientific research, help formulate more scientific and forward-looking treatment protocols, and enhance patient and public understanding and acceptance of the treatment options.

In conclusion, CAR T-cell therapy represents a novel approach to the treatment of autoimmune diseases, offering the potential for durable immune reconstitution and even a cure by specifically eliminating autoreactive B cells. Its remarkable efficacy has been demonstrated in refractory autoimmune diseases, such as SLE. Future innovations, including mRNA-engineered CAR T, “off-the-shelf” allogeneic CAR T-cell therapies, and combination CAR T-cell therapy are expected to enhance therapeutic outcomes, reduce toxicity, and lower costs. Additionally, risk stratification strategies will optimize personalized treatment, minimize adverse effects, and improve clinical safety and efficacy. Together, these advances position CAR T-cell therapy as a transformative frontier in autoimmune disease management, with the potential to achieve sustained remission and cures.