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

Abstract

Induced pluripotent stem cell-derived chimeric antigen receptor natural killer (iPSC-CAR-NK) cells are an evolving off-the-shelf cellular immunotherapy platform with potential for scalable manufacturing, product standardization, and multiplex engineering.This review summarizes recent progress in clinical-grade manufacturing, quality-attribute definition, and natural killer cell-adapted engineering strategies, including chimeric antigen receptor design, gene editing, tumor microenvironment adaptation, single-cell and multi-omics-guided optimization, and synthetic biologybased control.In addition, this review discusses recent progress in the application of iPSC-CAR-NK cells to hematologic malignancies and solid tumors and cautiously examines the early translational signal suggested by a single compassionate-use report in systemic sclerosis.To move beyond a descriptive listing of engineering strategies, we propose a multilevel analytical framework encompassing product definition, effector execution, tissue delivery, host interaction, and translational implementation.This framework is used to evaluate the functional roles, interrelationships, and limiting factors of engineering modules during clinical translation.Current evidence suggests manageable safety profiles and preliminary antitumor or immunomodulatory activity in some settings, but major barriers remain, including limited persistence, insufficient solidtumor infiltration, host immune clearance, antigen escape, multiplex-engineering risks, and immature quality-control and regulatory standards.