CAR-NK cell immunotherapy: a comprehensive review of engineering platforms, clinical applications in hematological and solid tumors

Abstract Chimeric antigen receptor–natural killer (CAR-NK) cells combine innate cytotoxicity with antigen-directed killing and promise as an immunotherapy with lower cytokine toxicity than CAR-T approaches. However, clinical translation is limited by challenges in transduction, persistence, tumor infiltration, and the immunosuppressive tumor microenvironment (TME). We performed a comprehensive literature review of recent preclinical and early-phase clinical studies, engineering strategies (CAR design, transduction technologies, gene-editing), manufacturing and expansion protocols, and trial outcomes in this review. We noted a reference to the advantages of CAR-NK, like multimodal killing (CAR-dependent and innate pathways), potential for allogeneic “off-the-shelf” use, and favorable early safety profiles. However, NK-specific obstacles persist: lower viral transduction efficiencies, short in vivo persistence, poor infiltration into solid tumors, and TME-mediated suppression (TGF-β, adenosine, metabolic stress). Engineering countermeasures such as IL-15 expression, checkpoint receptor knockout, chemokine receptor co-expression (e.g., CXCR1/4), DAP10/DAP12-based signaling domains, and non-viral delivery (transposons/CRISPR) have shown preclinical promise. CAR-NK therapy has developed from concept to a clinically actionable treatment line for hematologic malignancies and shows emerging potential in solid tumors when combined with TME-modulating strategies. This review provides robust evidence about CAR-NK therapies in hematological and solid tumors, with a great emphasis on the challenges they encounter, strategies, and innovative approaches to overcome these challenges, and forward-looking perspectives to improve future therapeutic CAR-NK designs and clinical outcomes.