CAR-engineered cell therapies: current understandings and future perspectives.

Chimeric antigen receptor (CAR)-engineered cell therapies represent a significant breakthrough in immunotherapy, initially in cancer and now expanding into diverse clinical fields. While originally developed for oncology, these platforms are increasingly being adapted for non-malignant conditions such as autoimmune disorders, infectious diseases, fibrosis, ageing-related issues, and organ transplants. This review details the evolution and diversification of CAR modalities- including CAR-T, CAR-NK, CAR-macrophages, and CAR-NKT cells- as well as emerging next-generation designs. It describes the key aspects of CAR structure, signalling pathways, and manufacturing, emphasising their application in treating hematologic and solid tumours, while considering challenges such as the tumour microenvironment (TME). The review also discusses expanding uses beyond cancer- such as CD19/BCMA-targeted CAR-T cells achieving long-term remission in lupus and rheumatoid arthritis without ongoing immunosuppression, CAR-NK approaches targeting HIV, CAR-Tregs enhancing transplant tolerance, and senolytic CARs reducing tissue fibrosis. Up-to-date research through 2025 is summarised to evaluate efficacy, safety, and adverse events, noting that CAR therapies show lower cytokine release syndrome (CRS) in autoimmune diseases. Innovations like off-the-shelf allogeneic products and logic-gated CARS are highlighted, alongside ongoing challenges such as manufacturing complexity, high costs, and antigen escape. Trials like KYV-101 for multiple sclerosis demonstrate continued progress and the potential of these therapies to translate into clinical practice. Overall, CAR-engineered treatments enable precise, programmable immune modulation, paving the way for advanced therapies across an expanding array of diseases.