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Gastrointestinal cancer is one of the leading health problems worldwide, with a high morbidity and mortality. To date, harnessing both the innate and adaptive immune system against cancer provides a selective and effective therapeutic strategy for patients. As a first line defense against cancer, natural killer (NK) cells can swiftly target and lyse tumor cells without prior activation. In addition to its pivotal role in innate immunity, NK cells also play unique roles in the adaptive immune system as it enhance anti-tumor adaptive immune responses through secretion of cytokines and retaining an immunological memory. All these characteristics make NK cell a promising anti-cancer agent for patients. In spite of scarce infiltration and impaired function of NK cells in tumors, and the fact that tumors easily develop resistant mechanisms to evade the attacks from endogenous NK cells, multiple strategies have been developed to boost anti-tumor effect of NK cells and abolish tumor resistance. Some examples include adoptive transfer of NK cells after ex vivo activation and expansion; restoration of NK cell function using immune checkpoint inhibitors, and monoclonal antibody or cytokine treatment. Preclinical data have shown encouraging results, suggesting that NK cells hold great potential in cancer therapy. In this review, we discuss NK cells’ cytotoxicity and modulation function in GI cancer and the current application in clinical therapy.