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

Abstract

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.