Gene-edited hematopoietic stem cells for leukemia and lymphoma treatment: a systematic review of preclinical and translational evidence.

Background: Hematopoietic stem cells (HSCs) are pivotal in regenerating the blood and immune systems and have been widely used in treating hematologic malignancies like leukemia and lymphoma. Advances in gene-editing technologies, such as CRISPR/Cas9 and lentiviral vectors, have enabled the modification of HSCs to enhance their therapeutic potential, offering a continuous source of tumor-targeting immune cells. However, challenges related to long-term engraftment, safety, and delivery mechanisms remain.

Methods: This systematic review, following PRISMA guidelines, evaluated 19 preclinical and translational studies on gene-edited HSCs for leukemia and lymphoma treatment. The review focused on gene-editing methodologies, preclinical outcomes, delivery challenges, and translational barriers. Databases such as PubMed, Web of Science, and Embase were searched using keywords related to gene editing, HSCs, and hematologic malignancies.

Findings: Gene-edited HSCs demonstrated promising preclinical efficacy, with CAR-engineered HSCs showing durable tumor clearance and multilineage immune reconstitution. Lentiviral vectors were the most common delivery method, but concerns about insertional mutagenesis persist. CRISPR/Cas9 offered precise editing but faced challenges with low homology-directed repair (HDR) efficiency in quiescent HSCs. Non-viral delivery methods, such as electroporation, showed potential for safer gene editing but require further optimization. Base editing technologies, while not requiring HDR, present their own delivery challenges that need to be addressed. Suicide gene strategies were effective in mitigating safety risks, while preconditioning regimens improved engraftment success.

Conclusions: Gene-edited HSCs hold significant promise for treating leukemia and lymphoma, offering long-term immune persistence and tumor clearance. However, challenges in gene delivery efficiency, safety, and engraftment must be addressed for clinical translation. Future research should focus on improving editing precision, scalable manufacturing, and robust safety monitoring to advance these therapies toward clinical trials.