The development of novel Chimeric Antigen Receptor (CAR) has significantly transformed cancer treatment, particularly through CAR-T and -NK cell therapies. This advancement has sparked growing interest from both the academic community and the general public. In the recent years, an exponential growth in the development of novel CAR designs for NK cells is formed with this trend expected to continue, because of unique property and advantages of NK cells over T cells. These diverse designs have empowered NK cell with enhanced functions, potentially amplifying their therapeutic effectiveness. This Research Topic aims to compile the latest concepts, designs, and rationales supported by evidence showcasing their in vitro and in vivo benefits. By doing so, it seeks to raise awareness regarding the principles behind successful CAR design for cancer therapy.

Most CAR-NK cells, whether derived from the NK92 cell line, primary NK cells, or iPSCs-derived NK cells, currently incorporate CAR designs adopted from CAR-T cells, highlighting a significant research gap in the development of NK-specific CARs and their potential implications. The challenges in the field of CAR-NK cell engineering and design for cancer patients encompass issues related to manufacturing, clinical application, immunosuppressive tumor microenvironment (solid and haematological malignancy) and delivery to tumors, all of which may differ from those encountered in CAR-T cells. Leveraging advanced tools such as single-cell RNA sequencing and multi-omics analysis holds promise for gaining deeper insights into NK or CAR-NK cell functions within the tumor microenvironment, ultimately leading to improved NK CAR designs.

This Research Topic encourages the submissions of Original Research articles (basic, translational, and clinical trial studies), Reviews, Perspectives, Comments, and Letters, including but not limited to the following topics:

• NK specific CAR designs, including the use novel structural domains or Cargos for engineering CAR-NK cell therapy:

• Multi-omics analysis on NK cells (preclinical or translational) leading to the discovery of novel genes for the design of next generation CAR-NK cells.

• Data from clinical trials with new CAR-NK cell concepts.

• Basic knowledge on how CARs interact with NK activating and inhibitory receptors or co-receptors.

• Clinical or preclinical studies for developing novel strategies to improve anti-tumor capacity of CAR-NK cells, especially in solid tumors.

Topic Editor Nathan Denlinger is in receipt of research funding from BMS. The other Topic Editors have no conflict of interest to declare with respect to this Research Topic.

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Frontiers in Immunology

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