CHIMERIC antigen receptor (CAR) immunotherapies are rapidly advancing beyond hematologic cancers, with new generations of CAR constructs and immune cell platforms showing promise across a wide spectrum of diseases. Recent developments suggest CAR-based treatments may soon benefit patients with solid tumors, autoimmune conditions, infectious diseases, and fibrotic disorders.
Originally developed to target blood cancers such as acute lymphoblastic leukemia and diffuse large B-cell lymphoma, CAR-T cell therapies have transformed outcomes in oncology. Innovations in CAR design, from first-generation constructs using CD3ζ signaling to more advanced iterations with co-stimulatory domains, have improved T cell persistence and enhanced antitumor activity. However, expanding CAR-T success to solid tumors remains complex due to antigen heterogeneity, immunosuppressive tumor microenvironments, and treatment-related toxicities like cytokine release syndrome and neurotoxicity.
To address these limitations, researchers are exploring CAR-engineered alternatives to T cells. These include CAR-natural killer cells, CAR-macrophages, and CAR-T regulatory cells, each offering unique biological properties that may overcome resistance mechanisms and improve safety. CAR-macrophages, for instance, could enhance tumor infiltration and promote phagocytosis, while CAR-Tregs offer potential for modulating immune responses in autoimmunity and transplant rejection.
In parallel, CAR-based approaches are being investigated for diseases well beyond cancer. Preclinical and early clinical research is exploring their use in autoimmune disorders, persistent infections, and fibrotic conditions, signaling a major shift in the therapeutic landscape.
Despite the progress, manufacturing and delivery remain key challenges. Gene modification methods, particularly viral vectors, raise concerns around scalability and safety. As a result, efforts are underway to develop non-viral gene delivery platforms to enable safer, more efficient CAR production.
Ongoing innovation in CAR design and application is central to realizing its full potential. As therapeutic targets broaden and cellular platforms diversify, CAR immunotherapies could soon play a central role across a range of clinical specialties.
Reference:
Sueangoen N, Prasongtanakij S. Emerging CAR immunotherapies: broadening therapeutic horizons beyond cancer. Clin Exp Med. 2025;25(1):274.
