Targeting the synovial engine: next-generation engineered immune cells to eradicate pathogenic FLS in rheumatoid arthritis, with safety-first, selective designs

Rheumatoid arthritis (RA) and associated inflammatory arthritides are characterized by chronic synovial inflammation that drives destructive pannus formation, eroding cartilage and bone. Current therapies (csDMARDs, bDMARDs, and tsDMARDs) target immune cells and cytokine pathways but yield low rates of full remission, and many patients with residual synovitis continue to damage their joints. Fibroblast-like synoviocytes (FLS) have emerged as key tumor-like mediators of RA. In the inflamed synovium, they expand, resist apoptosis, and secrete pro-inflammatory cytokines, chemokines, and proteases that sustain disease. Directly killing and/or reprogramming these pathogenic FLS is a promising complementary strategy. Recent advances in engineered cell therapies enable specific targeting of stromal cells. In this review, we will discuss novel CAR-based immune cells (CAR-T, CAR-NK, or CAR-macrophages) engineered to target FLS-specific antigens (e.g., fibroblast activation protein) and induce elimination or modulation of FLS. We advocate a primary "safety-first" translational roadmap that integrates features such as transient CAR expression, safety switches, hypoxia-responsive CAR constructs, and localized (intra-articular) delivery to enhance efficacy while avoiding systemic toxicity. Targeted cellular therapies based on this technology may reshape RA therapy as we know it, dismantling the synovial inflammation "engine" with precision and control.