Harnessing the potential of gene-editing technology to overcome the current bottlenecks of CAR-T cell therapy in T-cell malignancies.

T-cell malignancies (TCMs) include a diverse spectrum of hematologic cancers marked by complex biology and aggressive nature. Treating TCMs remains a critical unmet need in oncology with poor response to standard therapies. Chimeric antigen receptor (CAR)-T cell therapy is one of the most successful types of immunotherapy that has revolutionized cancer treatment, as evidenced by various approved products for CD19 B-cell malignancies and multiple myeloma. Nonetheless, due to some unique hurdles, such as the risk of CAR-T cell fratricide, product contamination with malignant cells, and severe T-cell aplasia, the translation of this treatment approach to TCMs has not been particularly successful. Moreover, irrespective of the type of treated cancer, CAR-T cell therapy can also present some complexities and potential side effects, such as cumbersome and costly manufacturing processes, impaired in vivo function, cytokine release syndrome (CRS), neurotoxicity, and leukemic transformation of CAR-T cells. Recent groundbreaking advances in gene-editing technology and the evolution of precise gene-editing tools such as the CRISPR/Cas9 system and its derivatives have opened a new way to overcoming the mentioned bottlenecks and paving the way for CAR-T cell therapy in TCMs. This review sheds light on how gene editing is being incorporated into CAR-T cell therapy to address current hurdles, enhance therapeutic efficacy, and improve the safety profile of CAR-T cell therapy in TCMs. Ongoing/conducted clinical trials are also discussed to provide a comprehensive view of the evolving landscape of genome-edited CAR-T cell therapy for TCMs.