The Pharmacology of CAR T Cell Therapy for Autoimmune Disease.

The future of TCR-Treg therapies is renewables.

Cell therapy has longstanding roots in haematopoietic stem cell transplantation and early immune cell transfers in infectious disease and transplantation, where patient- or donor-derived cells have achieved therapeutic benefit in selected contexts. The modern era has been driven largely by oncology, with engineered modalities such as tumour-infiltrating lymphocytes, CAR-T cells and TCR-engineered T cells delivering transformative responses but requiring complex, costly manufacturing. These platforms are now being adapted for autoimmune diseases to induce durable, antigen-specific immune tolerance, yet broad application is limited by safety concerns, process complexity and access. Non-engineered cell therapies for autoimmunity, including mesenchymal stem cells, polyclonal regulatory T cells and tolerogenic dendritic cells, have shown acceptable safety and proof-of-principle for immune re-education, but clinical responses have been modest and inconsistent, with limited scalability. Engineered approaches such as CAR-T cells can induce reversible B cell depletion in B cell-mediated rheumatic diseases but only addresses antibody-driven pathology and not T cell-mediated autoimmunity. TCR-engineered Tregs have emerged as a promising antigen-specific strategy, offering localized, antigen-linked suppression with bystander tolerance. Preclinical and early clinical data suggest superior potency, stability and disease control compared with polyclonal Tregs at similar or lower doses, but translation is constrained by the rarity and fragility of Tregs and by labour-intensive, CAR-T-like manufacturing. This review highlights emerging solutions for closed, automated and decentralised production, and discusses allogeneic approaches using gene-edited or banked Tregs with HLA engineering or matching. Together, these advances support the development of scalable, "off-the-shelf" TCR-Treg products with potential to provide safe, affordable tolerance-restoring therapies for autoimmune disease.

CAR-T cell therapy for autoimmune diseases: from immune suppression to immune resetting.

Autoimmune diseases are heterogeneous disorders marked by immune dysregulation, loss of self-tolerance, autoantibody production, and chronic inflammation. Although immunosuppressants and biologics have improved disease control, incomplete remission, relapse after withdrawal, cumulative toxicity, and failure to restore immune homeostasis remain common. Chimeric antigen receptor T-cell (CAR-T) therapy offers a potential strategy for refractory autoimmune diseases by selectively eliminating pathogenic immune compartments and providing a theoretical pathway toward target-dependent immune remodeling and immune resetting. This review summarizes immunopathogenesis and therapeutic gaps in representative autoimmune diseases, compares CAR-T applications in malignancies and autoimmunity, and evaluates emerging response endpoints, target-selection strategies, and safety considerations in autoimmune settings. Early clinical evidence suggests rapid disease control, autoantibody reduction, and immunosuppression-free remission in selected B-cell- or autoantibody-driven diseases. However, reported remission duration and response proportions remain limited by small cohorts, short follow-up, and disease-specific heterogeneity. The central unresolved question is whether durable remission can be achieved without persistent immune deficiency. Cytokine release syndrome, infection, hypogammaglobulinemia, relapse, impaired vaccine responses, T-cell fitness, manufacturing barriers, and cost remain key challenges. Future studies should define optimal targets, standardized remission endpoints, durable remission biomarkers, long-term safety, and the role of T-cell engagers.

CAR-Engineered Cell Therapies Beyond Cancer: Reprogramming Fibrosis and Immune-Mediated Inflammation.

Chimeric antigen receptor (CAR)-engineered cell therapies are being extended from hematological malignancies to autoimmune, inflammatory, and fibrotic diseases, although the maturity of evidence differs markedly among platforms and indications. Early clinical evidence from case reports, small case series, and early-phase trials suggests that CD19- or BCMA-directed CAR-T cells can induce deep B-cell or plasma-cell depletion and sustained remission in selected patients with refractory autoimmune diseases; however, their comparative efficacy, durability, and long-term safety remain incompletely defined. By contrast, CAR-based treatment of organ fibrosis remains predominantly preclinical. In animal models, transient in vivo CAR-T generation has attenuated fibrosis, whereas CAR-macrophage(CAR-M) approaches have demonstrated targeted phagocytosis and microenvironmental remodeling. Evidence for CAR-natural killer cells (CAR-NK) in non-oncological diseases is currently limited to preclinical studies and an individual-patient observation, despite their potential advantages for allogeneic and off-the-shelf manufacturing. This Review critically compares CAR-T, CAR-M, and CAR-NK platforms, examines emerging unconventional immune-cell and iPSC-derived products, and evaluates programmable and in vivo CAR-engineering strategies. We propose "controllable spatiotemporal reprogramming" as a framework linking target specificity, tissue distribution, activity duration, reversibility, manufacturing, and disease-specific safety requirements.

Regulatory T cells in autoimmune diseases: biological mechanisms, clinical translation, and translational challenges

Autoimmune diseases (ADs) are a group of inflammatory disorders triggered by aberrant immune responses against autoantigens and the breakdown of immune tolerance. Current therapeutic strategies, such as glucocorticoids and immunosuppressants, exert largely non-specific immunomodulation and are frequently associated with substantial adverse effects upon long-term administration. As such, these approaches are often insufficient to re-establish immune homeostasis. In recent years, regulatory T cell (Treg)-based therapeutics have undergone rapid advancement, with continuously updated therapeutic modalities broadening the application boundary of immune tolerance intervention. This review comprehensively outlines the progress of Treg-based therapeutics, spanning from fundamental biological research to translational applications in autoimmune diseases. We describe the developmental characteristics, suppressive machinery, and heterogeneity of Tregs, and highlight the preclinical and clinical advancements of diverse Treg therapeutic modalities, including polyclonal and antigen-specific Tregs, TCR-engineered Tregs, and CAR-Tregs. Furthermore, we emphasize current optimization strategies for enhancing Treg stability, antigen specificity, and in vivo fitness within inflammatory microenvironments. Additionally, we objectively address the major translational bottlenecks of Treg therapy and provide future perspectives to facilitate the clinical implementation of Treg-based immunotherapies for autoimmune diseases.

CAR T cell therapy beyond cancer: current status, challenges and future prospects

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized oncology, and its foundational logic—precise antigen recognition coupled with durable effector activity—extends naturally to chronic non-malignant diseases sustained by long-lived pathological cells. These include viral reservoirs, autoreactive B and plasma cells, activated fibroblasts, alloimmune clones, and senescent cells that remodel tissue niches and evade clearance by conventional therapies. This review highlights how CAR-based strategies can be adapted across diverse disease settings by redirecting engineered immune responses toward disease-sustaining cellular compartments. Co-stimulatory domains such as CD28, 4-1BB, and OX40 enhance persistence and effector function; programmed cell death protein 1 (PD-1)–CD28 switch receptors reverse inhibitory signaling; and cytokine-resistant CARs incorporating dominant-negative transforming growth factor-β (TGF-β) receptors maintain activity within suppressive microenvironments. We discuss these approaches across infections, including human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV); autoimmunity involving CD19- and B-cell maturation antigen (BCMA)-directed depletion strategies and CAR-engineered regulatory T cells (CAR-Tregs); fibrosis targeting fibroblast activation protein (FAP); hemophilia using B-cell antibody receptor (BAR)-CARs against factor VIII and factor IX inhibitors; transplantation employing human leukocyte antigen (HLA)-specific CAR-Tregs; and senescence-associated pathologies targeting urokinase plasminogen activator receptor (uPAR) and natural killer group 2D ligands (NKG2DLs). Early clinical experiences in systemic lupus erythematosus, systemic sclerosis, myositis, and multiple sclerosis, together with preclinical successes in chronic infections and fibrotic disease, demonstrate both feasibility and durable disease modification. By extending CAR-T therapy beyond oncology, these applications position programmable cellular immunotherapy as a broadly adaptable platform for eliminating persistent pathological cells, remodeling diseased tissue environments, and restoring long-term immune homeostasis.

In vivo CAR‑T therapy: recent progress and future directions