Breaking boundaries in ankylosing spondylitis: how innovative cell therapies reshape immunity, drive cutting-edge advances, and face future challenges

Abstract

Ankylosing spondylitis (AS) is a chronic autoimmune inflammatory disease primarily affecting the axial skeleton, characterized by joint erosion and ankylosis. AS significantly impacts quality of life, work capacity and mental health through chronic pain, stiffness and functional decline. Its pathogenesis is multifactorial, involving genetic predispositions, immunological dysregulation and environmental triggers. Current treatments, including nonsteroidal anti-inflammatory drugs and immunosuppressive agents, offer limited symptomatic relief and fail to improve long-term prognosis due to efficacy limitations and side effects. Recent advances in cell therapy, particularly mesenchymal stem cells (MSCs) and chimeric antigen receptor (CAR) T-cell therapy, demonstrate promise in addressing these limitations by providing immunomodulatory, anti-inflammatory and regenerative benefits. This review summarizes the pathogenesis of AS, the limitations of existing treatments and the clinical progress of MSC therapy, while exploring the potential of emerging CAR-based therapies.

Keywords: ankylosing spondylitis; autoimmune inflammation; chimeric antigen receptor T-cell therapy; clinical progress; mesenchymal stem cells; regenerative medicine.

Figure 1

Current treatments for AS. (A) Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs are the first-line treatment for AS, providing rapid relief of back pain, morning stiffness, and joint swelling. Commonly used NSAIDs include ibuprofen, naproxen, diclofenac and indomethacin. (B) Biological agents: Biological agents, including TNF-α inhibitors (TNFi), interleukin inhibitors, and JAK inhibitors (JAKi), constitute a targeted and efficacious therapeutic strategy for the management of AS. These agents modulate specific inflammatory pathways, offering a more precise treatment option for patients, particularly those who exhibit an inadequate response to NSAIDs. (C) Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs): Drugs like sulfasalazine and methotrexate are used for patients with peripheral joint involvement or those with contraindications to biologics. (D) Physical therapy: Physical therapy and surgical interventions are both essential components in the comprehensive management of AS. Physical therapy aims to enhance mobility and strength through personalized exercise regimens, while surgery is considered for severe cases to correct deformities or alleviate symptoms that have not responded to conservative treatments.

Figure 2

Characterization of MSCs. MSCs are derived from diverse tissue sources, including bone marrow, dental pulp, umbilical cord, and iPSCs. These cells exhibit specific surface marker expression profiles, such as CD105, CD90, and CD73, while lacking the expression of hematopoietic markers CD45, CD34, CD14 or CD11b, B cell markers CD79a or CD19, and HLA-DR. Notably, MSCs possess multipotent differentiation potential, enabling them to differentiate into various lineages, including adipocytes, osteoblasts, and chondrocytes.

Figure 3

Immunomodulatory mechanisms of MSCs and current clinical trials in AS. MSCs inhibit the proliferation of T cells, promote the differentiation of regulatory T cells (Tregs), suppress dendritic cell (DC) maturation, and induce macrophages to adopt an immunosuppressive phenotype. Additionally, several clinical trials are currently underway to validate the safety and efficacy of MSCs in AS, including the ongoing trial in our research group.

Figure 4

CAR-based immunotherapy for autoimmune diseases. The process of developing CAR-based therapies involves several key steps, starting from the selection of the cell source to the final deployment of engineered CAR cells.

Figure 5

Schematic overview of current and future directions in cell therapy for AS. The left side illustrates the current schematic, mechanisms, and future directions of MSC therapy for AS, while the right side depicts the possible schematic, mechanisms, and future directions of CAR-based therapy for AS. Solid lines indicate ongoing research, and dashed lines suggest potential future directions.