The Role of SAMHD1 in Viral Resistance and Transduction Efficiency Challenges in Pediatric Hematological Malignancies: Mechanistic Insights and Clinical Perspectives.

Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a dNTPase that regulates intracellular nucleotide pools, preserves genomic stability, and mediates intrinsic antiviral immunity. While its role in adult hematologic malignancies is established, its implications for pediatric leukemia-particularly acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)-remain underexplored. This review integrates transcriptomic, protein interaction, and immune correlation analyses to examine the dual role of SAMHD1 in pediatric hematological malignancies: as an antiviral restriction factor that impairs lentiviral gene therapy and as a therapeutic barrier that limits the efficacy of nucleoside analog-based chemotherapy. We compare emerging transduction-enhancing strategies, including Vpx delivery, SAMHD1 inhibition, and lipid nanoparticles, and evaluate their pediatric applicability. A conceptual schematic highlights the translational challenges unique to the developing immune and hematopoietic systems. Limitations of commonly used cellular models, such as THP-1 cells, are discussed alongside the need for pediatric-specific preclinical tools. We conclude by outlining a clinical translation roadmap and emphasizing the urgency of validating SAMHD1-targeted strategies in pediatric trials to ensure their safety, efficacy, and integration into future treatment paradigms.