Engineered CAR-NK Cells for the Treatment of Solid Tumors: Biological Foundations, Recognition Strategies, and Approaches to Enhance Antitumor Efficacy

Abstract

Cell-based immunotherapy has emerged as one of the most important innovative approaches in cancer research and treatment. Despite the success of chimeric antigen receptor-engineered T cells in certain hematological malignancies, extending this success to solid tumors is hindered by antigen heterogeneity, tumor immune escape, insufficient trafficking of therapeutic cells, hypoxia, metabolic dysfunction, and immunosuppressive factors. This review aimed to examine the biological foundations of the antitumor activity of natural killer cells and analyze the therapeutic potential of CAR-NK cells in solid tumors, with particular emphasis on triple-negative breast cancer and non-small cell lung cancer. In this review, data from scientific articles addressing NK-cell biology, chimeric antigen receptor structure and function, tumor target recognition, and factors limiting CAR-NK activity were qualitatively examined, categorized, and analyzed according to the major thematic areas of the study. The reviewed evidence indicates that the intrinsic capacity of NK cells to recognize stressed and malignant cells, combined with CAR-dependent specific recognition, enables multimodal antitumor responses. However, factors such as TGF-β, hypoxia, mitochondrial dysfunction, and heterogeneous antigen expression may reduce the persistence and cytotoxic activity of these cells. Multi-target strategies, reduced sensitivity to inhibitory pathways, support of cellular survival, and complementary interventions represent major approaches currently being investigated to improve CAR-NK function. Overall, the successful development of CAR-NK cells for solid tumors requires designs that account for tumor biology while preserving cellular function under restrictive conditions.