Emerging combined CAR-NK cell therapies in cancer treatment: Finding a dancing partner

In recent decades, immunotherapy with chimeric antigen receptors (CARs) has revolutionized cancer treatment and given hope where other cancer therapies have failed. CAR-natural killer (NK) cells are NK cells that have been engineered ex vivo with a CAR on the cell membrane with high specificity for specific target antigens of tumor cells. The impressive results of several studies suggest that CAR-NK cell therapy has significant potential and successful performance in cancer treatment. Despite its effectiveness, CAR-NK cell therapy can have significant challenges when it comes to treating cancer. These challenges include tumor heterogeneity, antigen escape, an immunosuppressive tumor microenvironment, limited tissue migration from blood, exhaustion of CAR-NK cells, and inhibition by immunosuppressive checkpoint molecule signaling, etc. In CAR-T cell therapy, the use of combined approaches has shown encouraging outcomes for tumor regression and improved cancer treatment compared to single therapies. Therefore, to overcome these significant challenges in CAR-NK cells, innovative combination therapies of CAR-NK cells with other conventional therapies (e.g., chemotherapy and radiotherapy) or other immunotherapies are needed to counteract the above challenges and thereby increase the activity of CAR-NK cells. This review comprehensively discusses various cancer-treatment approaches in combination with CAR-NK cell therapy in the hope of providing valuable insights that may improve cancer treatment in the near future.