Synovium-Restricted Armored PD-1-Targeted CAR-T Cells Reprogram Immunity and Resolve Experimental Arthritis

<jats:title>Abstract</jats:title> <jats:p> Despite major therapeutic advances, a substantial fraction of patients with autoimmune disease remains refractory to treatment. While B cell-targeted CAR-T therapies have shown considerable efficacy, the central contribution of pathogenic T cells to rheumatoid arthritis (RA) suggests that complementary T cell-directed strategies may enable deeper disease control. Using single-cell multi-omics of human RA and experimental models, <jats:italic>PDCD1</jats:italic> was identified as a selective marker of synovial disease-associated T cells. We developed PD-1-directed CAR-T cells that potently eliminate these cells <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> , leading to marked attenuation of synovitis in RA models. To limit off-target activity, we engineered NR4A2-driven CAR-responsive biosensors to restrict CAR activity to inflamed synovium. To couple anti-PD-1 CAR-mediated cytotoxicity with microenvironmental modulation, we further engineered these CAR-T cells to secrete soluble TNF receptor II (sTNFRii), counteracting baseline inflammation and CAR-induced IFN response and promoting a tissue-reparative myeloid state. PD-1-targeted CAR-T therapy thus represents a promising, specific, and safe strategy for autoimmune diseases involving disease-associated T cells. </jats:p>