Extracellular matrix–natural killer cell interactome: an uncharted territory in health and disease

Extracellular matrix (ECM) constantly undergoes remodeling to maintain the tissue homeostasis and an impaired ECM remodeling is a hallmark of many diseases, including cancer, infections, and inflammatory disorders. ECM has recently become recognized to regulate the immune response in peripheral tissues. Most immune cells express a diverse array of ECM receptors that, upon engagement by their cognate ECM ligands, can regulate their movement and effector functions. Natural killer (NK) cells are innate lymphocytes capable of mounting a swift cytotoxic immunity against cancer and virally infected cells using germline-encoded activating and inhibitory receptors. Regulation of NK cell effector function by ECM proteins in peripheral tissues is an emerging field with major implications for maintaining tolerance in normal tissues and controlling solid cancers, viral infections, and inflammatory diseases. The development of novel therapeutics targeting ECM-NK cell interplay represents a promising strategy to promote health and combat many diseases affecting solid organs.