Induced pluripotent stem cell-derived chimeric antigen receptor natural killer cells: Engineering innovations, translational hurdles and clinical prospects in immune therapy

Table 3 Evidence levels and translational maturity of induced pluripotent stem cell-derived chimeric antigen receptor natural killer cells across different disease contexts

Disease/application context	Representative product or strategy	Ref.	Current primary evidence type	Conclusions supported by current evidence	Major limitations	Translational maturity
Relapsed/refractory B-cell lymphoma	FT596; FT516 may serve as a reference for a non-CAR-engineered iPSC-derived NK-cell platform	[23,92]	Early phase I clinical studies	The FT596 study suggests early safety and preliminary antitumor activity signals of iPSC-derived CAR-NK cells in B-cell lymphoma. FT516 may serve as a clinical safety and feasibility reference for a non-CAR-engineered iPSC-NK platform	The sample size and follow-up duration are limited. Randomized controlled studies and direct comparisons with CAR-T cells, bispecific antibodies, or antibody-based combination therapies are lacking. FT516 is not a CAR-engineered product and therefore cannot serve as direct evidence for the efficacy of iPSC-CAR-NK cells	Early clinical stage
Multiple myeloma	FT576; multi-module iPSC-derived NK/CAR-NK strategies involving BCMA-CAR, hnCD16, IL-15-related support modules, CD38-related engineering, and other modifications	[50,91,114]	Early clinical data, interim disclosures, and related mechanistic studies	FT576-related data suggest that BCMA-targeted, multi-module engineered iPSC-derived NK/CAR-NK strategies have a degree of translational potential. Antigen-escape studies may help explain insufficient durability of response and relapse risk	Full peer-reviewed clinical publications and long-term follow-up remain limited. The duration of response, patterns of treatment failure, antigen escape involving BCMA, GPRC5D, and other targets, and comparative effectiveness against existing BCMA-targeted therapies remain unclear	Preliminary clinical evidence stage
AML	FT538; anti-TIM3 iPSC-CAR-NK cells; NKG2C-KE; a registered clinical study of CLL1/CD33-targeted iPSC-derived NK cells	[93-95]; ClinicalTrials.gov: NCT06367673	Preclinical studies, early clinical recruitment, or preliminary translational data	Current evidence supports the feasibility of target identification, engineering design, and functional validation for iPSC-derived NK/CAR-NK strategies in AML	Most evidence remains preclinical. AML targets are often shared with normal hematopoietic cells, creating a risk of on-target, off-tumor toxicity. In vivo safety, the therapeutic dose window, and the GMP scale-up pathway still require validation	Preclinical to early clinical exploratory stage
Solid tumors	CD276-, MSLN-, and GPC3-targeted iPSC-derived CAR-NK strategies, as well as iPSC-derived NK/CAR-NK strategies incorporating CCL19, CCR2B, IL-15, NKG2D, or other functional-enhancement modules	[21,35,98-100,106,107]	In vitro experiments, patient-derived organoid studies, animal models, and preclinical mechanistic studies	Current evidence suggests the preclinical feasibility, antigen-dependent killing, and some in vivo antitumor activity signals of iPSC-derived CAR-NK cells in solid tumors	Immunodeficient animal models have limited clinical predictive value. Stromal barriers, abnormal vasculature, immunosuppressive networks, metabolic stress, and antigen heterogeneity in human solid tumors have not been sufficiently modeled. Current evidence cannot be directly extrapolated to clinical efficacy	Mainly preclinical stage
Single-case compassionate-use exploration in systemic sclerosis; autoimmune-disease applications have not yet been established	CD19/BCMA dual-targeting iPSC-derived CAR-NK cells	[22,103]	Single compassionate-use case report and related commentary articles	The original case study suggests that B-cell depletion, clinical improvement, and manageable early safety signals were observed in this individual patient. This result should be regarded only as an early feasibility signal in the context of single-patient compassionate use	This is a single, uncontrolled case and cannot demonstrate reproducibility of efficacy. It should not be equated with disease-level proof of concept in systemic sclerosis, nor does it support broad extrapolation to other autoimmune diseases. Long-term safety, B-cell reconstitution, infection risk, host immune responses, and the respective contributions of CD19 and BCMA dual targeting still require validation in larger cohorts with longer follow-up	Single-case early translational signal

CAR: Chimeric antigen receptor; iPSCs: Induced pluripotent stem cells; NK: Natural killer; BCMA: B-cell maturation antigen; GPRC5D: G protein-coupled receptor class C group 5 member D; AML: Acute myeloid leukemia; GMP: Good Manufacturing Practice; IL: Interleukin; NKG2D: Natural killer group 2 member D.