AUTHOR=Xiang Yu , Dong Jiayi , Shao Lijuan , Chen Size 

TITLE=Chimeric antigen receptor natural killer cell therapy for solid tumors: mechanisms, clinical progress, and strategies to overcome the tumor microenvironment

JOURNAL=Experimental Biology and Medicine

VOLUME=Volume 250 - 2025

YEAR=2025

URL=https://www.ebm-journal.org/journals/experimental-biology-and-medicine/articles/10.3389/ebm.2025.10841

DOI=10.3389/ebm.2025.10841

ISSN=1535-3699

ABSTRACT=Natural killer (NK) cells represent a fundamental component of the innate immune system, endowed with the ability to identify and eradicate virus-infected and malignant cells. The advent of chimeric antigen receptor (CAR) technology has introduced innovative strategies for augmenting the antitumor potential of natural killer (NK) cells. Chimeric antigen receptor natural killer (CAR-NK) cells exert dual cytotoxic effects against tumor cells through CAR-mediated antigen-specific recognition in concert with the nonspecific cytolytic activity mediated by intrinsic NK receptors. This review critically evaluates the clinical progression of CAR-NK cells specifically against solid tumors, focusing on mechanisms to overcome the immunosuppressive tumor microenvironment (TME), the complexity of allogeneic manufacturing, and the latest engineering strategies for enhanced homing and persistence. Specifically, we emphasize the urgent need for robust Phase II/III clinical data and standardized Good Manufacturing Practice (GMP) protocols to realize the full potential of off-the-shelf allogeneic CAR-NK therapies. Additionally, we examine technological advancements and emerging directions addressing persistent challenges in this domain to offer theoretical underpinnings and research perspectives for the clinical deployment of CAR-NK cell therapy in solid tumor management.