Stem cell-derived immune cells in pediatric cancer therapy: From bench to bedside

Table 1 Summary of preclinical studies investigating stem cell-derived immune cell-based therapies in pediatric patients with cancer

Pediatric malignancy/classification	Stem cell-based platform and experimental models	Key preclinical outcomes	Mechanistic rationale and translational relevance	Ref.
Broad preclinical context	Advanced in vitro functional systems and pediatric xenograft models	Consistent antitumor efficacy with reproducible safety and mechanistic validation	Provides foundation for clinical translation	[39]
ALL	iPSC-derived CD19-CAR NK cells; NSG xenografts (Nalm-6, REH)	Potent cytotoxicity with tumor regression and survival benefit without toxicity	Comparable or superior to CAR-T with reduced GvHD risk	[53,55]
ALL - cytokine enhancement	IL-15-expressing CD19-CAR iPSC-NK; persistence xenografts	Enhanced persistence and durable tumor control without systemic cytokines	Autocrine IL-15 improves durability and clinical feasibility	[45]
Neuroblastoma	Activated and stem cell-derived NK cells; GD2-CAR iPSC-NK; PDX models	High NK sensitivity and robust tumor clearance	Missing-self recognition and GD2 tumor selectivity	[58,62]
Osteosarcoma	Primary samples; iPSC-NK; IL-15 activation	> 60% cytotoxicity in primary tumors with enhanced efficacy	HLA-independent recognition enables allogeneic strategies	[63-65]
Other pediatric solid tumors	NK receptor-ligand profiling; cytotoxicity screens	Variable but measurable NK responsiveness	Guides tumor-specific NK optimization	[55]
Mechanistic advantages	Engineered NK vs CAR-T comparative studies	Multi-receptor recognition limits antigen escape	Enhanced efficacy in heterogeneous tumors	[56]
Immunomodulatory effects	Immune coculture and in vivo remodeling models	Activation of dendritic cells and T-cell priming	Supports durable immune surveillance	[57]
Integrated translational outlook	Aggregate pediatric tumor models	Strong rationale for clinical translation	Guides biomarker-driven development strategies	[50-69]

The table provides an overview of preclinical research on stem cell-derived immune effector cells, with a focus on induced pluripotent stem cell-derived natural killer cells, which target both pediatric hematologic and solid malignancies. Data from in vitro functional assays and in vivo xenograft models demonstrate robust antitumor efficacy, favorable safety profiles, and insights into the underlying biological mechanisms. Genetic enhancements, including chimeric antigen receptor integration and cytokine pathway optimization, such as interleukin-15 expression, are highlighted for their role in increasing the cytotoxic potency, persistence, and durability of antitumor responses. Overall, these studies underscore the promising translational and clinical potential of stem cell-based immune therapies in pediatric cancer treatment. ALL: Acute lymphoblastic leukemia; iPSCs: Induced pluripotent stem cells; CAR: Chimeric antigen receptor; NK: Natural killer; GvHD: Graft-vs-host disease; IL: Interleukin; HLA: Human leukocyte antigen.