IN COLORECTAL CANCER (CRC), AN INCREASE IN TUMOR-INFILTRATING NATURAL KILLER (NK) CELLS IS ASSOCIATEDWITH PROLONGED SURVIVAL. HOWEVER, THE MECHANISMS USED BY NK CELLS TO CONTROL CRC DEVELOPMENTARE UNCLEAR. WE HAVE SHOWN THAT NK CELL DEPLETION ACCELERATES COLON TUMOR DEVELOPMENT IN MOUSECRC MODELS. FURTHER, SMAD4 EXPRESSION, A TUMOR SUPPRESSOR GENE, IN CIRCULATING NK CELLS IS SUPPRESSED IN UNTREATEDMETASTATIC CRC PATIENTS. MORE IMPORTANTLY, NK CELL-SPECIFIC SMAD4 GENE DELETION PROMOTES COLONTUMOR DEVELOPMENT IN TWO MOUSE CRC MODELS. MECHANISTICALLY, WE DISCOVERED THAT SMAD4DELETION IN NK CELLS DRAMATICALLY DECREASED NK CELL CYTOTOXICITY ASSOCIATED WITH REDUCEDEXPRESSION OF GRANZYME B (GZMB), AN IMPORTANT CYTOLYTIC FACTOR EXPRESSED IN CYTOTOXIC CELLS. OURIDENTIFICATION OF A ROLE FOR SMAD4 IN NK CELLS PROVIDES AN EXCELLENT OPPORTUNITY TO TARGET THE NKIMMUNE CELL LINEAGE IN CANCER. TOWARDS THAT END, WE FOUND THAT A BLACK RASPBERRY (BRB)-INTERVENTION ENHANCED NK CELL INFILTRATION IN TUMORS AND INCREASED THE LEVEL OF SEVERAL GUT BACTERIAMETABOLITES IN CRC PATIENTS. THESE METABOLITES UP-REGULATED SMAD4 AND GZMB EXPRESSION ANDENHANCED THE CYTOTOXICITY OF PRIMARY HUMAN NK CELLS. THEREFORE WE HYPOTHESIZE THAT BRB-DERIVEDGUT BACTERIA METABOLITES CAN SUPPRESS CRC BY ENHANCING SMAD4 EXPRESSION IN NK CELLS. WEPROPOSED TO DISSECT THE ROLE OF SMAD4 IN NK CELLS (AIM 1) AND TO DETERMINE WHICH BRB FRACTIONSPRODUCE THE GUT BACTERIA METABOLITES THAT CAN STIMULATE SMAD4 SIGNALING IN NK CELLS TO SUPPRESSCRC PROGRESSION (AIM 2). OUR STUDY PROVIDES NEW MECHANISMS SUPPORTING THE DEVELOPMENT OFTHESE METABOLITES FOR UP-REGULATING SMAD4 IN NK CELLS TO PREVENT CRC DEVELOPMENT.