CAR-NK cells for cancer immunotherapy: recent advances and future directions

Abstract

Natural Killer (NK) cells, intrinsic to the innate immune system, are pivotal in combating cancer due to their independent cytotoxic capabilities in antitumor immune response. Unlike predominant treatments that target T cell immunity, the limited success of T cell immunotherapy emphasizes the urgency for innovative approaches, with a spotlight on harnessing the potential of NK cells. Despite tumors adapting mechanisms to evade NK cell-induced cytotoxicity, there is optimism surrounding Chimeric Antigen Receptor (CAR) NK cells. This comprehensive review delves into the foundational features and recent breakthroughs in comprehending the dynamics of NK cells within the tumor microenvironment. It critically evaluates the potential applications and challenges associated with emerging CAR-NK cell therapeutic strategies, positioning them as promising tools in the evolving landscape of precision medicine. As research progresses, the unique attributes of CAR-NK cells offer a new avenue for therapeutic interventions, paving the way for a more effective and precise approach to cancer treatment.

Keywords: CAR-NK; adoptive cell transfer; cancer immunotherapy; natural killer cell; the tumor microenvironment.

Figure 1

The development of CAR-NK cells. The NK92 cell line is commonly used due to its ability to indefinitely expand in vitro. Primary NK cells can be directly isolated from peripheral blood mononuclear cells (PBMCs) or umbilical cord blood (UCB) using a NK cell isolation kit. These cells are then activated, genetically modified with CAR-expressing vectors, and expanded in NK cell-specific media with cytokines for clinical use. CD34+ hematopoietic progenitor cells (HPCs) can be differentiated into NK cells with a cytokine cocktail, and these cells are engineered with CAR before in vitro expansion and infusion. Induced pluripotent stem cells (iPSCs) have emerged as a promising “off-the-shelf” source for CAR-NK cells, given their unlimited proliferative capacity. iPSCs can differentiate into CD34+ HPCs, then into NK cells. Importantly, CAR-expressing vectors can be introduced into iPSCs, leading to CAR-iPSCs, which can further differentiate into CAR-HPCs and CAR-NK cells (Created with Biorender).