Natural Killer (NK) cells comprise a unique subset of lymphocytes with innate ability to detect and kill abnormal cells. Autologous NK cells and mature dendritic cells (DC) mutually activate each other and this interaction is believed to be important for NK cytotoxic activity against cancer cells. However, it has been shown that NK cell mediated lysis is greatly suppressed after interaction with stem cells [1-3]. It is believed that a phenomenon called split angery occurs in activated NK cells, causing the cells to lose their cytotoxic functions, but gain the ability to secrete cytokines. Understanding the interactions that take place between NK cells and the tumor microenvironment, and how these immune cells are able to specifically target virally infected and cancerous cells, but not healthy cells, is crucial for future developments of more effective preventative and therapeutic approaches in the battle of infectious diseases and cancer. In this study we hypothesized that oral and intestinal bacteria promote differentiation of the Oral Squamous Cancer Stem Cells (OSCSCs) and the Colorectal carcinoma cell line (HT29) through two primary mechanisms. The first, being through direct activation of OSCSCs and HT29s, and the second being through the induction of split anergy in interacting NK cells.Patient derived oral tumors and colorectal carcinomas were used in a standard 51Chromium release assay to determine their sensitivity or resistance against NK cell mediated lysis. The secretion of key cytokines by NK cells, such as Interferon- Gamma (IFN-γ), were determined using Enzyme-Linked Immunosorbent Assays (ELISAs). Experimental findings of this project demonstrate that the engagement of CD16 receptors on NK cells or interaction with monocytes, Fusobacterium nucleatum, bacterial LPS, or AKF-1 (a combination of eight bacterial strains) lead to the support of differentiation of stem cells via increased cytokine secretion by NK cells.