Advances in cell-based therapy for rheumatic immune diseases

Rheumatic immune diseases are chronic disorders driven by autoimmune dysregulation. Conventional pharmacotherapies, including nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs), have significant limitations such as systemic toxicity, infection risk, and failure to achieve sustained immunological remission. Cell-based therapies have recently emerged as groundbreaking strategies with the potential to reset immune tolerance and induce deep remission. This review systematically advances the understanding of two major cellular approaches: chimeric antigen receptor (CAR)-T cell therapy and stem cell therapy. CAR-T therapy targeting B-cell surface antigens, particularly CD19 and BCMA, induces rapid and profound B-cell depletion, leading to remarkable clinical responses in refractory systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), immune-mediated necrotizing myopathy (IMNM), and systemic sclerosis (SSc). Emerging innovations, including logic-gated CAR-T, RNA-engineered CAR-T (rCAR-T), allogeneic CRISPR-edited CAR-T, and CAR-natural killer (NK) cells, are enhancing safety, scalability, and accessibility. Fourth-generation CAR-T cells engineered to secrete anti-inflammatory cytokines (e.g., anti-IL-6, anti-TNFα) have shown feasibility in early-phase trials for RA. Parallel advancements in stem cell therapy demonstrate that mesenchymal stem cells (MSCs) modulate inflammatory microenvironments through paracrine signaling and cell-cell contact, improving outcomes in SLE, RA, multiple sclerosis (MS), and Sjögren′s syndrome (SS). Hematopoietic stem cell transplantation (HSCT) offers long-term, drug-free remission in severe refractory cases by resetting the immune system, with established efficacy in SSc and MS. Despite these breakthroughs, challenges including optimal target selection, long-term safety (e.g., infection risk), high costs, and manufacturing complexities remain. Future directions involve gene editing (CRISPR/Cas9), combination regimens, and personalized protocols to translate these therapies from bench to bedside. Collectively, cell-based therapies hold the potential to achieve deep remission or even functional cure for rheumatic immune diseases. <alternatives id="alt2"> </alternatives>