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.