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

Table 1 Comparison of chimeric antigen receptor T lymphocytes and chimeric antigen receptor natural killer cells

Characteristic	CAR-T cells	CAR-NK cells
Source	Usually derived from patients’ autologous T cells, but they may also be derived from T cells from healthy donors	Can be derived from peripheral blood, cord blood, iPSCs, the NK-92 cell line, bone marrow, placenta, and tumor-infiltrating NK cells
Cell type	T cells	NK cells
Mechanism of action	CAR-mediated antigen recognition activates T-cell cytotoxic effector function, thereby killing target cells	CAR-NK cells mediate CAR-directed killing while retaining the endogenous cytotoxic activity of NK cells; when CD16 is expressed, they can also mediate ADCC
Target specificity	Can be engineered to target various tumor-associated surface antigens	Can be engineered to target various tumor-associated surface antigens and may supplement antigen recognition through endogenous NK-cell receptors
Product manufacturing and application model	Autologous CAR-T cells usually require individualized manufacturing; allogeneic CAR-T cells require additional immune-safety engineering	Theoretically more amenable to standardized allogeneic manufacturing and “off-the-shelf” production, and may reduce variability caused by interindividual differences
Safety	May be associated with CRS, ICANS, GvHD, and other treatment-related toxicities	Existing studies suggest that the risks of CRS and neurotoxicity may be lower; however, systematic clinical monitoring and long-term safety validation are still required
Cost	The manufacturing process is complex, and individualized production usually results in relatively high costs	More compatible with scalable manufacturing models and may theoretically reduce costs in allogeneic application settings; however, this still requires validation in terms of GMP manufacturing data, quality-control costs, and real-world evidence
Immune escape and in vivo limitations	Susceptible to antigen loss, T-cell exhaustion, and the immunosuppressive tumor microenvironment	Endogenous NK-cell recognition and ADCC may partially complement CAR-mediated recognition; these cells do not carry the risk of αβ TCR-mediated GvHD, but may still face host immune clearance, insufficient in vivo persistence, limited tumor infiltration, and suppression by the tumor microenvironment

CAR: Chimeric antigen receptor; NK: Natural killer; iPSCs: Induced pluripotent stem cells; ADCC: Antibody-dependent cellular cytotoxicity; CRS: Cytokine release syndrome; ICANS: Immune effector cell-associated neurotoxicity syndrome; GvHD: Graft-vs-host disease; GMP: Good Manufacturing Practice; TCR: T cell receptor.