Beyond CAR-T and oncology: broadening chimeric antigen receptor technologies across cell types and diseases

Abstract

Chimeric antigen receptor (CAR)-engineered immune cells have revolutionized cancer immunotherapy, expanding from the established success of CAR-T cells to a diverse array of cellular platforms. While seven Food and Drug Administration-approved CAR-T cell products demonstrate unprecedented efficacy in hematologic malignancies, significant limitations persist, including severe inflammatory toxicities, resistance in solid tumors, and manufacturing barriers. These challenges have catalyzed extensive research to extend CAR engineering into alternative effector cell types, such as unconventional T cell subsets, natural killer (NK) cells, macrophages, neutrophils, and dendritic cells, as well as non-immune platforms. Each cell type exhibits distinct antitumor mechanisms, persistence profiles, safety characteristics, and manufacturing requirements, positioning them to address complementary therapeutic needs. This review provides a comprehensive overview of diverse CAR-engineered cellular platforms, encompassing their biological properties, advantages, sourcing strategies, and manufacturing processes, alongside current clinical progress and optimization approaches. Beyond oncology, these platforms have demonstrated significant potential in treating autoimmune diseases, infections, cardiac fibrosis, and senescence-associated disorders. By leveraging distinct immune and non-immune cell types to mediate cytotoxicity or suppress pathogenic cells, CAR technology provides versatile therapeutic avenues across varied disease contexts. Through synthesis of recent advances in CAR platform diversity, this review identifies opportunities for targeted optimization and explores future directions for broadening CAR-based therapeutic applications.

Keywords

chimeric antigen receptor / CAR-engineered cells / adoptive cell therapy / immunotherapy / cancer treatment

Acknowledgements

The authors regret that it was not possible to include many other interesting citations in the field due to limited space. Images were created with Adobe Illustrator.

Author contributions

Xiaohong Liu (Conceptualization, Investigation, Methodology), Hongye Gao (Investigation, Methodology), and Jianhua Yu (Conceptualization, Investigation, Methodology, Project administration).

Conflicts of interest

J.Y. is a co-founder of CytoImmune Therapeutics, which has an interest in NK cell-based therapies. In addition, as an Editorial Board Member of Precision Clinical Medicine, the corresponding author J.Y. was blinded from reviewing and making decision on this manuscript. All other authors declare no competing interests.

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