Tehran University of Medical Sciences Immunology and Genetics Journal 2645-4831 8 0 2025 02 24 39 49 Maryam Sadeghi School of Medicine, Tehran University of Medical Sciences, Tehran, Iran Kosar Asnaashari Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Children’s Medical Center Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Department of Pediatrics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran 2025 02 24 2025 02 24 Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are the two common types of pediatric leukemia. Despite conventional therapy, treatment failure and poor survival are observed in children with leukemia. Adoptive cell therapy needs to get more advanced to overcome high-risk pediatric leukemia. Dendritic Cells and cytokines are two influential factors in natural killer (NK) cell therapy. However, no defined effect of killer-cell immunoglobulin-like receptor (KIR) on NK cells has been obtained. Moreover, a combination of checkpoint fusion protein with chimeric antigen receptor (CAR) T-cell therapy can highly improve the anti-tumor function of T cells. Biomarkers, namely serum cytokines, MicroRNAs (miRs), ADAM6, CD200 and CD123, sGRP78 and CXCR4, and Semaphorin 4D (Sema4D) are helpful in finding patients with a risk of relapse, and an appropriate treatment approach, or act as a potential targetable marker. In this review, the clinical and preclinical/animal studies with the purpose of diagnosis and treatment of relapsed or refractory pediatric leukemia are discussed. Preclinical/animal ACT studies have shown improvements in the treatment of children with high-risk leukemia. However, clinical studies are required to verify the efficacy of these approaches for the treatment of childhood leukemia. https://igj.tums.ac.ir/index.php/igj/article/view/192 https://igj.tums.ac.ir/index.php/igj/article/download/192/169