Chimeric antigen receptor (CAR) T-cell therapy, established in oncology, leverages precise antigen recognition combined with durable effector activity. The conceptual foundation of CAR therapy—directing immune cells to eliminate specific, disease-sustaining cell populations—can be applied to a range of chronic non-malignant conditions driven by long-lived pathological cells. These compartments include viral reservoirs, autoreactive B and plasma cells, activated fibroblasts, alloimmune clones, and senescent cells that remodel tissue environments and evade conventional treatments. The reviewed work frames CAR-based strategies as adaptable tools to redirect engineered immune responses toward such disease-sustaining cellular populations.
The review summarizes several design features used to improve CAR performance in suppressive or chronic disease settings. Selection of co-stimulatory domains such as CD28, 4-1BB, and OX40 is highlighted as a means to enhance T-cell persistence and effector function. Receptor architectures that modify inhibitory signaling are discussed, including PD-1–CD28 switch receptors that convert an inhibitory PD-1 signal into a costimulatory input. To overcome suppressive microenvironments, CARs incorporating dominant-negative transforming growth factor-β (TGF-β) receptors are presented as a strategy to maintain activity where TGF-β would otherwise inhibit effector cells. These engineering approaches are described as modular adaptations that can be tuned to the biology of the target tissue and disease.
CAR-based approaches are considered for chronic infectious diseases where long-lived cellular reservoirs maintain pathology. The review specifically mentions human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV) as examples. In these contexts, redirecting CAR-expressing lymphocytes toward infected cells that harbor persistent virus could complement or extend the effects of antiviral therapies by physically eliminating the reservoir compartments that sustain long-term infection.
Autoimmune conditions are addressed through strategies that deplete pathogenic B-lineage cells or re-establish immune regulation. CD19- and B-cell maturation antigen (BCMA)-directed CARs are discussed as depletion strategies targeting autoreactive B and plasma cells. In parallel, engineered regulatory T cells (CAR-Tregs) are proposed to restore tolerance by delivering antigen-specific immune suppression. These complementary approaches—cellular depletion and antigen-specific regulation—illustrate how CAR technology can be tailored to both remove pathogenic clones and reprogram immune control mechanisms in autoimmunity.
Fibrotic diseases driven by activated stromal cells are identified as promising targets for CAR interventions. The review highlights fibroblast activation protein (FAP) as a fibrotic target amenable to CAR-mediated depletion of pathogenic fibroblasts. By removing or modulating these activated fibroblasts, CAR approaches aim to interrupt the cellular drivers of fibrotic remodeling and potentially remodel diseased tissue niches.
The review describes specialized CAR formats for hemophilia and transplantation. For hemophilia complicated by inhibitory antibodies to factor VIII or IX, B-cell antibody receptor (BAR) CARs are noted as a strategy to target inhibitor-producing B cells. In transplantation, human leukocyte antigen (HLA)-specific CAR-Tregs are proposed to suppress alloimmune responses and promote graft tolerance by delivering antigen-restricted regulatory activity.
Senescent cells that persist in tissues and contribute to age-related and chronic pathologies are discussed as CAR targets. The review mentions urokinase plasminogen activator receptor (uPAR) and NKG2D ligands as candidate senescence-associated markers for CAR-mediated clearance. Targeting senescent cells with CAR-expressing effectors is presented as a means to remodel tissue microenvironments and relieve senescence-driven dysfunction.
The authors summarize emerging clinical and preclinical data supporting feasibility and, in some cases, durable disease modification. Early clinical experiences are cited for systemic lupus erythematosus, systemic sclerosis, myositis, and multiple sclerosis. Preclinical successes are reported across chronic infections and fibrotic disease models. Collectively, these findings are used to argue that extending CAR-T therapy beyond oncology is practical and has yielded signals of therapeutic benefit in diverse settings.
While the review emphasizes the adaptability of CAR technology, it also recognizes implicit challenges inherent to applying powerful cellular therapies outside oncology. These include selecting disease-specific targets that distinguish pathological from protective cells, avoiding on-target off-tissue toxicity, and managing immunologic and microenvironmental inhibitors of CAR function. Engineering strategies such as co-stimulatory tuning, inhibitory-signal conversion (PD-1–CD28 switches), and resistance to suppressive cytokines (dominant-negative TGF-β receptors) are presented as partial solutions that require further optimization. The review positions programmable CAR platforms as promising but still evolving tools that must be refined for safety, durability, and disease-specific efficacy.
Extending CAR-T therapy beyond cancer reframes programmable cellular immunotherapy as a broadly adaptable platform for eliminating persistent pathological cells, remodeling diseased tissue environments, and restoring long-term immune homeostasis. The review compiles engineering strategies and disease-targeting examples—spanning infections, autoimmunity, fibrosis, hemophilia, transplantation, and senescence—while noting early clinical and preclinical evidence of feasibility. The authors report no competing interests. Details such as specific trial outcomes, quantitative efficacy measures, and comprehensive safety data were not reported in the abstract and would require consultation of the full review and referenced studies for clinical decision-making.