Abstract: Increased release of TNF-α in the tumor microenvironment was found to be inhibitory for the function of cytotoxic immune effectors while being supportive of the survival and function of tumor target cells. Tumors of the oral origin induce significant release of TNF-α. TNF-α knockout mice were shown to be resistant to chemically induced skin carcinogenesis. Thus, I hypothesized that the life span of the immune effectors is expanded in the TNF-/- mice and therefore, in absence of TNF-α, activated immune effectors remain viable for longer periods of time and are capable of lysing more tumor cells. In absence of TNF-α, levels of cytotoxicity were significantly increased in IL-2 treated splenocytes and NK cells against MOK L2D1+/p53-/- and YAC-1 tumor cells. Splenocytes and NK cells from TNF-/- mice as compared to TNF+/+ mice released significant amounts of IFN-γ when co-cultured with MOK L2D1+/p53-/-. Splenocytes from TNF-/- mice exhibited significantly higher survival when treated with HEMA and F. nucleatum in comparison to TNF+/+ cells survival. Indeed, addition of IL-2 alone resulted in increased survival and expansion of splenocytes and NK cells from TNF-/- mice when compared to TNF+/+ mice. Addition of exogenous TNF-α to untreated or IL-2 treated splenocytes significantly decreased survival and function of splenocytes and NK cells from both TNF+/+ and TNF-/- mice. However, survival and function of splenocytes and NK cells from TNF-/- mice were always higher when compared to TNF+/+ mice. The long term goal of my research is to find strategies to restore functional competency and expand the numbers of cytotoxic immune effector cells in order to improve the poor treatment outcomes and survival rates for oral cancer patients. I provide evidence that presence of TNF-α decreases the function of cytotoxic immune effectors, weakens their survival and diminishes the secretion of tumor inhibitory cytokines such as IFN-γ. Therefore, in the absence of TNF-α, activated immune effectors will remain viable for longer periods of time, mediating increased cytotoxicity against tumor cells in addition to increased release of tumor inhibitory cytokines. Strategies to neutralize TNF-α production may be beneficial in treatment and prevention of oral cancers.