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

Table 2 Comparison of induced pluripotent stem cell-derived chimeric antigen receptor natural killer cells with major competing off-the-shelf cellular immunotherapy platforms

Platform	Main source/product form	Key features/potential advantages	Major limitations	Key differences compared with iPSC-derived CAR-NK cells	Maturity of clinical translation
Peripheral blood-derived CAR-NK cells	Peripheral blood NK cells from healthy donors or patients, followed by ex vivo expansion and CAR engineering	Relatively strong natural cytotoxic activity; mature cell source; relatively preserved primary NK-cell effector functions; an existing clinical research basis	Limited frequency of NK cells in the starting material; expansion efficiency and functional status are affected by donor variability; donor-to-donor differences may lead to insufficient batch-to-batch consistency; large-scale standardized manufacturing remains challenging	Cell function is closer to that of primary NK cells, but standardization, scalability, and batch-to-batch consistency are generally weaker than those of the iPSC-derived platform	Early clinical exploration has been reported
Cord blood-derived CAR-NK cells	Cord blood NK cells or cord blood-derived NK precursor cells, followed by expansion and CAR engineering	Relatively low immunogenicity; suitable for allogeneic application; relatively standardized sample source; potential for off-the-shelf development	Limited cell numbers from a single cord blood unit; ex vivo expansion and maturation still require optimization; inter-sample variability may affect manufacturing consistency; limited in vivo persistence	Existing clinical development basis, but difficult to achieve long-term, stable, large-scale production comparable to that enabled by a single-clone-derived iPSC	Early clinical exploration
NK-92 cell line-derived CAR-NK cells	NK-92 cell line engineered with a CAR	Easy to expand; relatively stable manufacturing workflow; suitable for early process development and mechanistic validation	Cell line origin raises safety concerns; pre-infusion irradiation is usually required, limiting in vivo proliferation and persistence; intrinsic lack of CD16 results in insufficient ADCC capacity	Standardized expansion is relatively straightforward, but in vivo persistence and clinical applicability are limited by pre-infusion irradiation and cell line-related properties	Preclinical research and early clinical exploration
iPSC-derived CAR-NK cells	Single-clone-derived iPSCs subjected to CAR introduction and multiplex engineering, followed by differentiation into NK cells	Master cell banks can be established; theoretically favorable for scalable and standardized manufacturing with improved batch-to-batch consistency; amenable to multiplex gene editing; suitable for modular engineering	Complex differentiation workflow; high manufacturing cost and quality-control requirements; genetic stability, residual undifferentiated cells, and risks associated with multiplex editing must be controlled; long-term in vivo persistence and real-world cost advantages still require validation	Compared with primary NK and NK-92 platforms, this platform has development potential in platform-based manufacturing and multiplex engineering, but its comparative clinical advantages still require further validation	Early-stage clinical validation
Allogeneic CAR-T cells	Healthy donor-derived T cells engineered with a CAR, often requiring TCR- and HLA-related gene editing	Strong antigen-specific cytotoxic capacity of T cells; relatively mature CAR-T development experience; potential for off-the-shelf development	Need to address TCR-mediated GvHD, host anti-graft responses, immune rejection, and gene-editing safety; CRS/ICANS may still occur; multiplex editing increases regulatory and quality-control complexity	Compared with iPSC-derived CAR-NK cells, CAR-T cell therapy has more extensive clinical development experience, but allogeneic T cell-related immune safety concerns and editing requirements are greater	Multiple early clinical studies are ongoing
γδ T-cell and CAR-γδ T-cell therapies	Peripheral blood- or tissue-derived γδ T cells, followed by ex vivo expansion or CAR engineering	MHC-unrestricted recognition; both innate-like and adaptive immune features; theoretically lower risk of GvHD; ability to recognize stress-associated antigens	Marked subset heterogeneity of γδ T cells; expansion stability and engineering efficiency require optimization; functional differences among subsets are substantial; consistency of clinical efficacy still requires validation	Compared with iPSC-derived CAR-NK cells, γδ T cells have T cell-like cytotoxicity and tissue homing- or tissue residency-related features, but product standardization and batch-to-batch consistency remain challenging	Preclinical to early clinical exploration

The “key features/potential advantages” listed in this table include theoretical platform advantages and technical features reported in early studies; they should not be equated with clinical superiority demonstrated by prospective randomized clinical trials. Some platforms should be understood as off-the-shelf or potentially off-the-shelf cellular immunotherapy strategies. The information in this table was synthesized from studies and reviews related to peripheral blood- and cord blood-derived chimeric antigen receptor (CAR)-natural killer (NK) cells, NK-92 cell line-derived CAR-NK cells, induced pluripotent stem cell (iPSC)-derived CAR-NK cells, allogeneic CAR-T cells, and γδ T-cell and CAR-γδ T-cell therapies[8-10,18,22-24,40,42,43,45,47,48,50-52]. The potential advantages of iPSC-derived CAR-NK cells in scalable manufacturing, batch-to-batch consistency, and cost control still require further validation through Good Manufacturing Practice manufacturing data, clinical studies, and real-world evidence. iPSCs: Induced pluripotent stem cells; CAR: Chimeric antigen receptor; NK: Natural killer; ADCC: Antibody-dependent cellular cytotoxicity; CRS: Cytokine release syndrome; ICANS: Immune effector cell-associated neurotoxicity syndrome; TCR: T cell receptor; HLA: Human leukocyte antigen; GvHD: Graft-vs-host disease.