Addressing Natural Killer Cell Dysfunction and Plasticity in Cell-Based Cancer Therapeutics

SIMPLE SUMMARY: The natural killer (NK) cells of the immune system identify and remove stressed, infected, or cancerous cells in the body. This anti-tumor functionality has been harnessed through promising cell-based therapies that involve the isolation, expansion, activation, and delivery of NK cells for the treatment of several cancers. A variety of techniques have been developed to genetically modify or otherwise improve the activity of these therapeutic NK cells. However, certain elements of the tumor microenvironment are known to alter NK cell functions, suppressing their killing capacity and enhancing their ability to stimulate the formation of blood vessels that support tumor growth. This review summarizes current NK cell-based cancer therapies and discusses improvements that are being pursued to address these mechanisms of tumor-mediated NK cell suppression. ABSTRACT: Natural killer (NK) cells are cytotoxic group 1 innate lymphoid cells (ILC), known for their role as killers of stressed, cancerous, and virally infected cells. Beyond this cytotoxic function, NK cell subsets can influence broader immune responses through cytokine production and have been linked to central roles in non-immune processes, such as the regulation of vascular remodeling in pregnancy and cancer. Attempts to exploit the anti-tumor functions of NK cells have driven the development of various NK cell-based therapies, which have shown promise in both pre-clinical disease models and early clinical trials. However, certain elements of the tumor microenvironment, such as elevated transforming growth factor (TGF)-β, hypoxia, and indoalemine-2,3-dioxygenase (IDO), are known to suppress NK cell function, potentially limiting the longevity and activity of these approaches. Recent studies have also identified these factors as contributors to NK cell plasticity, defined by the conversion of classical cytotoxic NK cells into poorly cytotoxic, tissue-resident, or ILC1-like phenotypes. This review summarizes the current approaches for NK cell-based cancer therapies and examines the challenges presented by tumor-linked NK cell suppression and plasticity. Ongoing efforts to overcome these challenges are discussed, along with the potential utility of NK cell therapies to applications outside cancer.