Recent advances in CAR-MSCs: the new engine of cellular immunotherapy evolution

In recent years, the development of chimeric antigen receptor (CAR) technology has greatly promoted the progress of cellular immunotherapy. Among them, CAR-T cell therapy has shown remarkable clinical effects in the treatment of hematological malignancies. However, this therapy still faces a series of challenges, including immunogenicity, toxic side effects, and insufficient maintenance of long-term efficacy. The latest research progress has extended CAR technology to mesenchymal stem cells (MSCs), and the resulting CAR-MSCs combine the precise targeting ability of CAR molecules with the inherent immunomodulatory, tissue homing, and regenerative repair properties of MSCs, providing a new therapeutic strategy for cancer and immune-related diseases. This review examines the engineering design, biological characteristics, and applications of CAR-MSCs in oncology and immune-related disorder therapy. Preclinical studies have shown their effectiveness against glioblastoma, Ewing sarcoma, acute myeloid leukemia, and lung cancer, as well as graft-versus-host disease, through TRAIL secretion, bispecific antibody production, and Treg induction. Despite promising results, significant hurdles persist in CAR-MSC manufacturing scalability, cell persistence, heterogeneous MSC tissue sourcing, and undefined application protocols, all of which are critical for clinical translation. We investigated corresponding strategies, including nonviral gene delivery, metabolic engineering, senescence-resistant MSC clones, and microenvironment-specific activation. Standardized production workflows incorporating rigorous quality control are essential for future applications. CAR-MSCs represent a paradigm shift in precision immunotherapy by providing dual therapeutic modalities for cancer and immune disorders. Fully unlocking their therapeutic potential will require interdisciplinary efforts to overcome biological and technical barriers while advancing combination therapies.