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Simple Summary  Natural killer (NK) cells are innate lymphocytes that play a key role in the anti-tumor response by their ability to recognize and kill transformed cells. Their relevance in anti-tumor immune surveillance is demonstrated by the various strategies that tumor cells develop to switch off NK-mediated responses, often aimed at diminishing activating NK receptor function. In this review, we describe the expression and role of the main activating NK receptors displayed by circulating NK cells and/or tumor-infiltrating NK cells in patients with solid tumors of the gastrointestinal tract that affect the pancreas, stomach, and colon-rectus. These malignancies are characterized by high incidence and low survival rate at advanced stages, thus novel therapeutic approaches are urgently needed. We suggest that the most promising immunotherapies are those aimed at restoring activating NK cell receptors dysfunction and overcoming immune suppression exerted by the tumor microenvironment.    Abstract  Human NK cells can control tumor growth and metastatic spread thanks to their powerful cytolytic activity which relies on the expression of an array of activating receptors. Natural cytotoxicity receptors (NCRs) NKG2D and DNAM-1 are those non-HLA-specific activating NK receptors that are mainly involved in sensing tumor transformation by the recognition of different ligands, often stress-induced molecules, on the surface of cancer cells. Tumors display several mechanisms aimed at dampening/evading NK-mediated responses, a relevant fraction of which is based on the downregulation of the expression of activating receptors and/or their ligands. In this review, we summarize the role of the main non-HLA-specific activating NK receptors, NCRs, NKG2D and DNAM-1, in controlling tumor growth and metastatic spread in solid malignancies affecting the gastrointestinal tract with high incidence in the world population, i.e., pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and gastric cancer (GC), also describing the phenotypic and functional alterations induced on NK cells by their tumor microenvironment.

Role of the Main Non HLA-Specific Activating NK Receptors in Pancreatic, Colorectal and Gastric Tumors Surveillance